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ResearchIn-Press PreviewGeneticsNeuroscience Open Access | 10.1172/JCI185791

Microglial GRB2 is essential for brain ventriculogenesis and CSF homeostasis

Phan Q. Duy,1 Benjamin C. Reeves,2 Huanxing Sun,3 Xueyan Peng,3 Pazhanichamy Kalailingam,4 Garrett Allington,2 Evan Dennis,1 Le Thi Hao,5 Lei Wang,6 David Rufino-Ramos,4 Shujuan Zhao,7 Qiang Li,1 Neel H. Mehta,1 William C. Davalan,1 Mason Blacker,8 Anthony J. Piscopo,8 Shozeb Haider,9 Baojian Fan,1 Kedous Y. Mekbib,2 Shuai Shao,3 Carol Nelson-Williams,10 TuKiet T. Lam,11 Benjamin P. Kleinstiver,4 Patricia L. Musolino,12 Seth L. Alper,13 Sheng Chih Jin,7 Erica L. Herzog,3 and Kristopher T. Kahle1

1Department of Neurosurgery, Massachusetts General Hospital, Harvard Medical School, Boston, United States of America

2Department of Neurosurgery, Yale University School of Medicine, New Haven, United States of America

3Section of Pulmonary, Critical Care, and Sleep Medicine, Department of Inte, Yale University School of Medicine, New Haven, United States of America

4Center for Genomic Medicine, Massachusetts General Hospital, Boston, United States of America

5Department of Pediatrics, Yale University School of Medicine, New Haven, United States of America

6Department of Neuroscience, University of Virginia School of Medicine, Charlottesville, United States of America

7Department of Genetics, School of Medicine, Washington University, St. Louis, United States of America

8Department of Neurosurgery, Barrow Neurological Institute, Phoenix, United States of America

9School of Pharmacy, University College London, London, United Kingdom

10Department of Genetics, Yale University School of Medicine, New Haven, United States of America

11Department of Molecular Biophysics and Biochemistry, Yale University, New Haven, United States of America

12Department of Neurology, Massachusetts General Hospital, Harvard Medical School, Boston, United States of America

13Division of Nephrology and Center for Vascular Biology Research, Department, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, United States of America

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1Department of Neurosurgery, Massachusetts General Hospital, Harvard Medical School, Boston, United States of America

2Department of Neurosurgery, Yale University School of Medicine, New Haven, United States of America

3Section of Pulmonary, Critical Care, and Sleep Medicine, Department of Inte, Yale University School of Medicine, New Haven, United States of America

4Center for Genomic Medicine, Massachusetts General Hospital, Boston, United States of America

5Department of Pediatrics, Yale University School of Medicine, New Haven, United States of America

6Department of Neuroscience, University of Virginia School of Medicine, Charlottesville, United States of America

7Department of Genetics, School of Medicine, Washington University, St. Louis, United States of America

8Department of Neurosurgery, Barrow Neurological Institute, Phoenix, United States of America

9School of Pharmacy, University College London, London, United Kingdom

10Department of Genetics, Yale University School of Medicine, New Haven, United States of America

11Department of Molecular Biophysics and Biochemistry, Yale University, New Haven, United States of America

12Department of Neurology, Massachusetts General Hospital, Harvard Medical School, Boston, United States of America

13Division of Nephrology and Center for Vascular Biology Research, Department, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, United States of America

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1Department of Neurosurgery, Massachusetts General Hospital, Harvard Medical School, Boston, United States of America

2Department of Neurosurgery, Yale University School of Medicine, New Haven, United States of America

3Section of Pulmonary, Critical Care, and Sleep Medicine, Department of Inte, Yale University School of Medicine, New Haven, United States of America

4Center for Genomic Medicine, Massachusetts General Hospital, Boston, United States of America

5Department of Pediatrics, Yale University School of Medicine, New Haven, United States of America

6Department of Neuroscience, University of Virginia School of Medicine, Charlottesville, United States of America

7Department of Genetics, School of Medicine, Washington University, St. Louis, United States of America

8Department of Neurosurgery, Barrow Neurological Institute, Phoenix, United States of America

9School of Pharmacy, University College London, London, United Kingdom

10Department of Genetics, Yale University School of Medicine, New Haven, United States of America

11Department of Molecular Biophysics and Biochemistry, Yale University, New Haven, United States of America

12Department of Neurology, Massachusetts General Hospital, Harvard Medical School, Boston, United States of America

13Division of Nephrology and Center for Vascular Biology Research, Department, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, United States of America

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1Department of Neurosurgery, Massachusetts General Hospital, Harvard Medical School, Boston, United States of America

2Department of Neurosurgery, Yale University School of Medicine, New Haven, United States of America

3Section of Pulmonary, Critical Care, and Sleep Medicine, Department of Inte, Yale University School of Medicine, New Haven, United States of America

4Center for Genomic Medicine, Massachusetts General Hospital, Boston, United States of America

5Department of Pediatrics, Yale University School of Medicine, New Haven, United States of America

6Department of Neuroscience, University of Virginia School of Medicine, Charlottesville, United States of America

7Department of Genetics, School of Medicine, Washington University, St. Louis, United States of America

8Department of Neurosurgery, Barrow Neurological Institute, Phoenix, United States of America

9School of Pharmacy, University College London, London, United Kingdom

10Department of Genetics, Yale University School of Medicine, New Haven, United States of America

11Department of Molecular Biophysics and Biochemistry, Yale University, New Haven, United States of America

12Department of Neurology, Massachusetts General Hospital, Harvard Medical School, Boston, United States of America

13Division of Nephrology and Center for Vascular Biology Research, Department, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, United States of America

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1Department of Neurosurgery, Massachusetts General Hospital, Harvard Medical School, Boston, United States of America

2Department of Neurosurgery, Yale University School of Medicine, New Haven, United States of America

3Section of Pulmonary, Critical Care, and Sleep Medicine, Department of Inte, Yale University School of Medicine, New Haven, United States of America

4Center for Genomic Medicine, Massachusetts General Hospital, Boston, United States of America

5Department of Pediatrics, Yale University School of Medicine, New Haven, United States of America

6Department of Neuroscience, University of Virginia School of Medicine, Charlottesville, United States of America

7Department of Genetics, School of Medicine, Washington University, St. Louis, United States of America

8Department of Neurosurgery, Barrow Neurological Institute, Phoenix, United States of America

9School of Pharmacy, University College London, London, United Kingdom

10Department of Genetics, Yale University School of Medicine, New Haven, United States of America

11Department of Molecular Biophysics and Biochemistry, Yale University, New Haven, United States of America

12Department of Neurology, Massachusetts General Hospital, Harvard Medical School, Boston, United States of America

13Division of Nephrology and Center for Vascular Biology Research, Department, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, United States of America

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1Department of Neurosurgery, Massachusetts General Hospital, Harvard Medical School, Boston, United States of America

2Department of Neurosurgery, Yale University School of Medicine, New Haven, United States of America

3Section of Pulmonary, Critical Care, and Sleep Medicine, Department of Inte, Yale University School of Medicine, New Haven, United States of America

4Center for Genomic Medicine, Massachusetts General Hospital, Boston, United States of America

5Department of Pediatrics, Yale University School of Medicine, New Haven, United States of America

6Department of Neuroscience, University of Virginia School of Medicine, Charlottesville, United States of America

7Department of Genetics, School of Medicine, Washington University, St. Louis, United States of America

8Department of Neurosurgery, Barrow Neurological Institute, Phoenix, United States of America

9School of Pharmacy, University College London, London, United Kingdom

10Department of Genetics, Yale University School of Medicine, New Haven, United States of America

11Department of Molecular Biophysics and Biochemistry, Yale University, New Haven, United States of America

12Department of Neurology, Massachusetts General Hospital, Harvard Medical School, Boston, United States of America

13Division of Nephrology and Center for Vascular Biology Research, Department, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, United States of America

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1Department of Neurosurgery, Massachusetts General Hospital, Harvard Medical School, Boston, United States of America

2Department of Neurosurgery, Yale University School of Medicine, New Haven, United States of America

3Section of Pulmonary, Critical Care, and Sleep Medicine, Department of Inte, Yale University School of Medicine, New Haven, United States of America

4Center for Genomic Medicine, Massachusetts General Hospital, Boston, United States of America

5Department of Pediatrics, Yale University School of Medicine, New Haven, United States of America

6Department of Neuroscience, University of Virginia School of Medicine, Charlottesville, United States of America

7Department of Genetics, School of Medicine, Washington University, St. Louis, United States of America

8Department of Neurosurgery, Barrow Neurological Institute, Phoenix, United States of America

9School of Pharmacy, University College London, London, United Kingdom

10Department of Genetics, Yale University School of Medicine, New Haven, United States of America

11Department of Molecular Biophysics and Biochemistry, Yale University, New Haven, United States of America

12Department of Neurology, Massachusetts General Hospital, Harvard Medical School, Boston, United States of America

13Division of Nephrology and Center for Vascular Biology Research, Department, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, United States of America

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1Department of Neurosurgery, Massachusetts General Hospital, Harvard Medical School, Boston, United States of America

2Department of Neurosurgery, Yale University School of Medicine, New Haven, United States of America

3Section of Pulmonary, Critical Care, and Sleep Medicine, Department of Inte, Yale University School of Medicine, New Haven, United States of America

4Center for Genomic Medicine, Massachusetts General Hospital, Boston, United States of America

5Department of Pediatrics, Yale University School of Medicine, New Haven, United States of America

6Department of Neuroscience, University of Virginia School of Medicine, Charlottesville, United States of America

7Department of Genetics, School of Medicine, Washington University, St. Louis, United States of America

8Department of Neurosurgery, Barrow Neurological Institute, Phoenix, United States of America

9School of Pharmacy, University College London, London, United Kingdom

10Department of Genetics, Yale University School of Medicine, New Haven, United States of America

11Department of Molecular Biophysics and Biochemistry, Yale University, New Haven, United States of America

12Department of Neurology, Massachusetts General Hospital, Harvard Medical School, Boston, United States of America

13Division of Nephrology and Center for Vascular Biology Research, Department, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, United States of America

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1Department of Neurosurgery, Massachusetts General Hospital, Harvard Medical School, Boston, United States of America

2Department of Neurosurgery, Yale University School of Medicine, New Haven, United States of America

3Section of Pulmonary, Critical Care, and Sleep Medicine, Department of Inte, Yale University School of Medicine, New Haven, United States of America

4Center for Genomic Medicine, Massachusetts General Hospital, Boston, United States of America

5Department of Pediatrics, Yale University School of Medicine, New Haven, United States of America

6Department of Neuroscience, University of Virginia School of Medicine, Charlottesville, United States of America

7Department of Genetics, School of Medicine, Washington University, St. Louis, United States of America

8Department of Neurosurgery, Barrow Neurological Institute, Phoenix, United States of America

9School of Pharmacy, University College London, London, United Kingdom

10Department of Genetics, Yale University School of Medicine, New Haven, United States of America

11Department of Molecular Biophysics and Biochemistry, Yale University, New Haven, United States of America

12Department of Neurology, Massachusetts General Hospital, Harvard Medical School, Boston, United States of America

13Division of Nephrology and Center for Vascular Biology Research, Department, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, United States of America

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1Department of Neurosurgery, Massachusetts General Hospital, Harvard Medical School, Boston, United States of America

2Department of Neurosurgery, Yale University School of Medicine, New Haven, United States of America

3Section of Pulmonary, Critical Care, and Sleep Medicine, Department of Inte, Yale University School of Medicine, New Haven, United States of America

4Center for Genomic Medicine, Massachusetts General Hospital, Boston, United States of America

5Department of Pediatrics, Yale University School of Medicine, New Haven, United States of America

6Department of Neuroscience, University of Virginia School of Medicine, Charlottesville, United States of America

7Department of Genetics, School of Medicine, Washington University, St. Louis, United States of America

8Department of Neurosurgery, Barrow Neurological Institute, Phoenix, United States of America

9School of Pharmacy, University College London, London, United Kingdom

10Department of Genetics, Yale University School of Medicine, New Haven, United States of America

11Department of Molecular Biophysics and Biochemistry, Yale University, New Haven, United States of America

12Department of Neurology, Massachusetts General Hospital, Harvard Medical School, Boston, United States of America

13Division of Nephrology and Center for Vascular Biology Research, Department, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, United States of America

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1Department of Neurosurgery, Massachusetts General Hospital, Harvard Medical School, Boston, United States of America

2Department of Neurosurgery, Yale University School of Medicine, New Haven, United States of America

3Section of Pulmonary, Critical Care, and Sleep Medicine, Department of Inte, Yale University School of Medicine, New Haven, United States of America

4Center for Genomic Medicine, Massachusetts General Hospital, Boston, United States of America

5Department of Pediatrics, Yale University School of Medicine, New Haven, United States of America

6Department of Neuroscience, University of Virginia School of Medicine, Charlottesville, United States of America

7Department of Genetics, School of Medicine, Washington University, St. Louis, United States of America

8Department of Neurosurgery, Barrow Neurological Institute, Phoenix, United States of America

9School of Pharmacy, University College London, London, United Kingdom

10Department of Genetics, Yale University School of Medicine, New Haven, United States of America

11Department of Molecular Biophysics and Biochemistry, Yale University, New Haven, United States of America

12Department of Neurology, Massachusetts General Hospital, Harvard Medical School, Boston, United States of America

13Division of Nephrology and Center for Vascular Biology Research, Department, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, United States of America

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1Department of Neurosurgery, Massachusetts General Hospital, Harvard Medical School, Boston, United States of America

2Department of Neurosurgery, Yale University School of Medicine, New Haven, United States of America

3Section of Pulmonary, Critical Care, and Sleep Medicine, Department of Inte, Yale University School of Medicine, New Haven, United States of America

4Center for Genomic Medicine, Massachusetts General Hospital, Boston, United States of America

5Department of Pediatrics, Yale University School of Medicine, New Haven, United States of America

6Department of Neuroscience, University of Virginia School of Medicine, Charlottesville, United States of America

7Department of Genetics, School of Medicine, Washington University, St. Louis, United States of America

8Department of Neurosurgery, Barrow Neurological Institute, Phoenix, United States of America

9School of Pharmacy, University College London, London, United Kingdom

10Department of Genetics, Yale University School of Medicine, New Haven, United States of America

11Department of Molecular Biophysics and Biochemistry, Yale University, New Haven, United States of America

12Department of Neurology, Massachusetts General Hospital, Harvard Medical School, Boston, United States of America

13Division of Nephrology and Center for Vascular Biology Research, Department, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, United States of America

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1Department of Neurosurgery, Massachusetts General Hospital, Harvard Medical School, Boston, United States of America

2Department of Neurosurgery, Yale University School of Medicine, New Haven, United States of America

3Section of Pulmonary, Critical Care, and Sleep Medicine, Department of Inte, Yale University School of Medicine, New Haven, United States of America

4Center for Genomic Medicine, Massachusetts General Hospital, Boston, United States of America

5Department of Pediatrics, Yale University School of Medicine, New Haven, United States of America

6Department of Neuroscience, University of Virginia School of Medicine, Charlottesville, United States of America

7Department of Genetics, School of Medicine, Washington University, St. Louis, United States of America

8Department of Neurosurgery, Barrow Neurological Institute, Phoenix, United States of America

9School of Pharmacy, University College London, London, United Kingdom

10Department of Genetics, Yale University School of Medicine, New Haven, United States of America

11Department of Molecular Biophysics and Biochemistry, Yale University, New Haven, United States of America

12Department of Neurology, Massachusetts General Hospital, Harvard Medical School, Boston, United States of America

13Division of Nephrology and Center for Vascular Biology Research, Department, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, United States of America

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1Department of Neurosurgery, Massachusetts General Hospital, Harvard Medical School, Boston, United States of America

2Department of Neurosurgery, Yale University School of Medicine, New Haven, United States of America

3Section of Pulmonary, Critical Care, and Sleep Medicine, Department of Inte, Yale University School of Medicine, New Haven, United States of America

4Center for Genomic Medicine, Massachusetts General Hospital, Boston, United States of America

5Department of Pediatrics, Yale University School of Medicine, New Haven, United States of America

6Department of Neuroscience, University of Virginia School of Medicine, Charlottesville, United States of America

7Department of Genetics, School of Medicine, Washington University, St. Louis, United States of America

8Department of Neurosurgery, Barrow Neurological Institute, Phoenix, United States of America

9School of Pharmacy, University College London, London, United Kingdom

10Department of Genetics, Yale University School of Medicine, New Haven, United States of America

11Department of Molecular Biophysics and Biochemistry, Yale University, New Haven, United States of America

12Department of Neurology, Massachusetts General Hospital, Harvard Medical School, Boston, United States of America

13Division of Nephrology and Center for Vascular Biology Research, Department, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, United States of America

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1Department of Neurosurgery, Massachusetts General Hospital, Harvard Medical School, Boston, United States of America

2Department of Neurosurgery, Yale University School of Medicine, New Haven, United States of America

3Section of Pulmonary, Critical Care, and Sleep Medicine, Department of Inte, Yale University School of Medicine, New Haven, United States of America

4Center for Genomic Medicine, Massachusetts General Hospital, Boston, United States of America

5Department of Pediatrics, Yale University School of Medicine, New Haven, United States of America

6Department of Neuroscience, University of Virginia School of Medicine, Charlottesville, United States of America

7Department of Genetics, School of Medicine, Washington University, St. Louis, United States of America

8Department of Neurosurgery, Barrow Neurological Institute, Phoenix, United States of America

9School of Pharmacy, University College London, London, United Kingdom

10Department of Genetics, Yale University School of Medicine, New Haven, United States of America

11Department of Molecular Biophysics and Biochemistry, Yale University, New Haven, United States of America

12Department of Neurology, Massachusetts General Hospital, Harvard Medical School, Boston, United States of America

13Division of Nephrology and Center for Vascular Biology Research, Department, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, United States of America

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1Department of Neurosurgery, Massachusetts General Hospital, Harvard Medical School, Boston, United States of America

2Department of Neurosurgery, Yale University School of Medicine, New Haven, United States of America

3Section of Pulmonary, Critical Care, and Sleep Medicine, Department of Inte, Yale University School of Medicine, New Haven, United States of America

4Center for Genomic Medicine, Massachusetts General Hospital, Boston, United States of America

5Department of Pediatrics, Yale University School of Medicine, New Haven, United States of America

6Department of Neuroscience, University of Virginia School of Medicine, Charlottesville, United States of America

7Department of Genetics, School of Medicine, Washington University, St. Louis, United States of America

8Department of Neurosurgery, Barrow Neurological Institute, Phoenix, United States of America

9School of Pharmacy, University College London, London, United Kingdom

10Department of Genetics, Yale University School of Medicine, New Haven, United States of America

11Department of Molecular Biophysics and Biochemistry, Yale University, New Haven, United States of America

12Department of Neurology, Massachusetts General Hospital, Harvard Medical School, Boston, United States of America

13Division of Nephrology and Center for Vascular Biology Research, Department, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, United States of America

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1Department of Neurosurgery, Massachusetts General Hospital, Harvard Medical School, Boston, United States of America

2Department of Neurosurgery, Yale University School of Medicine, New Haven, United States of America

3Section of Pulmonary, Critical Care, and Sleep Medicine, Department of Inte, Yale University School of Medicine, New Haven, United States of America

4Center for Genomic Medicine, Massachusetts General Hospital, Boston, United States of America

5Department of Pediatrics, Yale University School of Medicine, New Haven, United States of America

6Department of Neuroscience, University of Virginia School of Medicine, Charlottesville, United States of America

7Department of Genetics, School of Medicine, Washington University, St. Louis, United States of America

8Department of Neurosurgery, Barrow Neurological Institute, Phoenix, United States of America

9School of Pharmacy, University College London, London, United Kingdom

10Department of Genetics, Yale University School of Medicine, New Haven, United States of America

11Department of Molecular Biophysics and Biochemistry, Yale University, New Haven, United States of America

12Department of Neurology, Massachusetts General Hospital, Harvard Medical School, Boston, United States of America

13Division of Nephrology and Center for Vascular Biology Research, Department, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, United States of America

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1Department of Neurosurgery, Massachusetts General Hospital, Harvard Medical School, Boston, United States of America

2Department of Neurosurgery, Yale University School of Medicine, New Haven, United States of America

3Section of Pulmonary, Critical Care, and Sleep Medicine, Department of Inte, Yale University School of Medicine, New Haven, United States of America

4Center for Genomic Medicine, Massachusetts General Hospital, Boston, United States of America

5Department of Pediatrics, Yale University School of Medicine, New Haven, United States of America

6Department of Neuroscience, University of Virginia School of Medicine, Charlottesville, United States of America

7Department of Genetics, School of Medicine, Washington University, St. Louis, United States of America

8Department of Neurosurgery, Barrow Neurological Institute, Phoenix, United States of America

9School of Pharmacy, University College London, London, United Kingdom

10Department of Genetics, Yale University School of Medicine, New Haven, United States of America

11Department of Molecular Biophysics and Biochemistry, Yale University, New Haven, United States of America

12Department of Neurology, Massachusetts General Hospital, Harvard Medical School, Boston, United States of America

13Division of Nephrology and Center for Vascular Biology Research, Department, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, United States of America

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1Department of Neurosurgery, Massachusetts General Hospital, Harvard Medical School, Boston, United States of America

2Department of Neurosurgery, Yale University School of Medicine, New Haven, United States of America

3Section of Pulmonary, Critical Care, and Sleep Medicine, Department of Inte, Yale University School of Medicine, New Haven, United States of America

4Center for Genomic Medicine, Massachusetts General Hospital, Boston, United States of America

5Department of Pediatrics, Yale University School of Medicine, New Haven, United States of America

6Department of Neuroscience, University of Virginia School of Medicine, Charlottesville, United States of America

7Department of Genetics, School of Medicine, Washington University, St. Louis, United States of America

8Department of Neurosurgery, Barrow Neurological Institute, Phoenix, United States of America

9School of Pharmacy, University College London, London, United Kingdom

10Department of Genetics, Yale University School of Medicine, New Haven, United States of America

11Department of Molecular Biophysics and Biochemistry, Yale University, New Haven, United States of America

12Department of Neurology, Massachusetts General Hospital, Harvard Medical School, Boston, United States of America

13Division of Nephrology and Center for Vascular Biology Research, Department, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, United States of America

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1Department of Neurosurgery, Massachusetts General Hospital, Harvard Medical School, Boston, United States of America

2Department of Neurosurgery, Yale University School of Medicine, New Haven, United States of America

3Section of Pulmonary, Critical Care, and Sleep Medicine, Department of Inte, Yale University School of Medicine, New Haven, United States of America

4Center for Genomic Medicine, Massachusetts General Hospital, Boston, United States of America

5Department of Pediatrics, Yale University School of Medicine, New Haven, United States of America

6Department of Neuroscience, University of Virginia School of Medicine, Charlottesville, United States of America

7Department of Genetics, School of Medicine, Washington University, St. Louis, United States of America

8Department of Neurosurgery, Barrow Neurological Institute, Phoenix, United States of America

9School of Pharmacy, University College London, London, United Kingdom

10Department of Genetics, Yale University School of Medicine, New Haven, United States of America

11Department of Molecular Biophysics and Biochemistry, Yale University, New Haven, United States of America

12Department of Neurology, Massachusetts General Hospital, Harvard Medical School, Boston, United States of America

13Division of Nephrology and Center for Vascular Biology Research, Department, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, United States of America

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1Department of Neurosurgery, Massachusetts General Hospital, Harvard Medical School, Boston, United States of America

2Department of Neurosurgery, Yale University School of Medicine, New Haven, United States of America

3Section of Pulmonary, Critical Care, and Sleep Medicine, Department of Inte, Yale University School of Medicine, New Haven, United States of America

4Center for Genomic Medicine, Massachusetts General Hospital, Boston, United States of America

5Department of Pediatrics, Yale University School of Medicine, New Haven, United States of America

6Department of Neuroscience, University of Virginia School of Medicine, Charlottesville, United States of America

7Department of Genetics, School of Medicine, Washington University, St. Louis, United States of America

8Department of Neurosurgery, Barrow Neurological Institute, Phoenix, United States of America

9School of Pharmacy, University College London, London, United Kingdom

10Department of Genetics, Yale University School of Medicine, New Haven, United States of America

11Department of Molecular Biophysics and Biochemistry, Yale University, New Haven, United States of America

12Department of Neurology, Massachusetts General Hospital, Harvard Medical School, Boston, United States of America

13Division of Nephrology and Center for Vascular Biology Research, Department, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, United States of America

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1Department of Neurosurgery, Massachusetts General Hospital, Harvard Medical School, Boston, United States of America

2Department of Neurosurgery, Yale University School of Medicine, New Haven, United States of America

3Section of Pulmonary, Critical Care, and Sleep Medicine, Department of Inte, Yale University School of Medicine, New Haven, United States of America

4Center for Genomic Medicine, Massachusetts General Hospital, Boston, United States of America

5Department of Pediatrics, Yale University School of Medicine, New Haven, United States of America

6Department of Neuroscience, University of Virginia School of Medicine, Charlottesville, United States of America

7Department of Genetics, School of Medicine, Washington University, St. Louis, United States of America

8Department of Neurosurgery, Barrow Neurological Institute, Phoenix, United States of America

9School of Pharmacy, University College London, London, United Kingdom

10Department of Genetics, Yale University School of Medicine, New Haven, United States of America

11Department of Molecular Biophysics and Biochemistry, Yale University, New Haven, United States of America

12Department of Neurology, Massachusetts General Hospital, Harvard Medical School, Boston, United States of America

13Division of Nephrology and Center for Vascular Biology Research, Department, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, United States of America

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1Department of Neurosurgery, Massachusetts General Hospital, Harvard Medical School, Boston, United States of America

2Department of Neurosurgery, Yale University School of Medicine, New Haven, United States of America

3Section of Pulmonary, Critical Care, and Sleep Medicine, Department of Inte, Yale University School of Medicine, New Haven, United States of America

4Center for Genomic Medicine, Massachusetts General Hospital, Boston, United States of America

5Department of Pediatrics, Yale University School of Medicine, New Haven, United States of America

6Department of Neuroscience, University of Virginia School of Medicine, Charlottesville, United States of America

7Department of Genetics, School of Medicine, Washington University, St. Louis, United States of America

8Department of Neurosurgery, Barrow Neurological Institute, Phoenix, United States of America

9School of Pharmacy, University College London, London, United Kingdom

10Department of Genetics, Yale University School of Medicine, New Haven, United States of America

11Department of Molecular Biophysics and Biochemistry, Yale University, New Haven, United States of America

12Department of Neurology, Massachusetts General Hospital, Harvard Medical School, Boston, United States of America

13Division of Nephrology and Center for Vascular Biology Research, Department, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, United States of America

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1Department of Neurosurgery, Massachusetts General Hospital, Harvard Medical School, Boston, United States of America

2Department of Neurosurgery, Yale University School of Medicine, New Haven, United States of America

3Section of Pulmonary, Critical Care, and Sleep Medicine, Department of Inte, Yale University School of Medicine, New Haven, United States of America

4Center for Genomic Medicine, Massachusetts General Hospital, Boston, United States of America

5Department of Pediatrics, Yale University School of Medicine, New Haven, United States of America

6Department of Neuroscience, University of Virginia School of Medicine, Charlottesville, United States of America

7Department of Genetics, School of Medicine, Washington University, St. Louis, United States of America

8Department of Neurosurgery, Barrow Neurological Institute, Phoenix, United States of America

9School of Pharmacy, University College London, London, United Kingdom

10Department of Genetics, Yale University School of Medicine, New Haven, United States of America

11Department of Molecular Biophysics and Biochemistry, Yale University, New Haven, United States of America

12Department of Neurology, Massachusetts General Hospital, Harvard Medical School, Boston, United States of America

13Division of Nephrology and Center for Vascular Biology Research, Department, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, United States of America

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1Department of Neurosurgery, Massachusetts General Hospital, Harvard Medical School, Boston, United States of America

2Department of Neurosurgery, Yale University School of Medicine, New Haven, United States of America

3Section of Pulmonary, Critical Care, and Sleep Medicine, Department of Inte, Yale University School of Medicine, New Haven, United States of America

4Center for Genomic Medicine, Massachusetts General Hospital, Boston, United States of America

5Department of Pediatrics, Yale University School of Medicine, New Haven, United States of America

6Department of Neuroscience, University of Virginia School of Medicine, Charlottesville, United States of America

7Department of Genetics, School of Medicine, Washington University, St. Louis, United States of America

8Department of Neurosurgery, Barrow Neurological Institute, Phoenix, United States of America

9School of Pharmacy, University College London, London, United Kingdom

10Department of Genetics, Yale University School of Medicine, New Haven, United States of America

11Department of Molecular Biophysics and Biochemistry, Yale University, New Haven, United States of America

12Department of Neurology, Massachusetts General Hospital, Harvard Medical School, Boston, United States of America

13Division of Nephrology and Center for Vascular Biology Research, Department, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, United States of America

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1Department of Neurosurgery, Massachusetts General Hospital, Harvard Medical School, Boston, United States of America

2Department of Neurosurgery, Yale University School of Medicine, New Haven, United States of America

3Section of Pulmonary, Critical Care, and Sleep Medicine, Department of Inte, Yale University School of Medicine, New Haven, United States of America

4Center for Genomic Medicine, Massachusetts General Hospital, Boston, United States of America

5Department of Pediatrics, Yale University School of Medicine, New Haven, United States of America

6Department of Neuroscience, University of Virginia School of Medicine, Charlottesville, United States of America

7Department of Genetics, School of Medicine, Washington University, St. Louis, United States of America

8Department of Neurosurgery, Barrow Neurological Institute, Phoenix, United States of America

9School of Pharmacy, University College London, London, United Kingdom

10Department of Genetics, Yale University School of Medicine, New Haven, United States of America

11Department of Molecular Biophysics and Biochemistry, Yale University, New Haven, United States of America

12Department of Neurology, Massachusetts General Hospital, Harvard Medical School, Boston, United States of America

13Division of Nephrology and Center for Vascular Biology Research, Department, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, United States of America

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1Department of Neurosurgery, Massachusetts General Hospital, Harvard Medical School, Boston, United States of America

2Department of Neurosurgery, Yale University School of Medicine, New Haven, United States of America

3Section of Pulmonary, Critical Care, and Sleep Medicine, Department of Inte, Yale University School of Medicine, New Haven, United States of America

4Center for Genomic Medicine, Massachusetts General Hospital, Boston, United States of America

5Department of Pediatrics, Yale University School of Medicine, New Haven, United States of America

6Department of Neuroscience, University of Virginia School of Medicine, Charlottesville, United States of America

7Department of Genetics, School of Medicine, Washington University, St. Louis, United States of America

8Department of Neurosurgery, Barrow Neurological Institute, Phoenix, United States of America

9School of Pharmacy, University College London, London, United Kingdom

10Department of Genetics, Yale University School of Medicine, New Haven, United States of America

11Department of Molecular Biophysics and Biochemistry, Yale University, New Haven, United States of America

12Department of Neurology, Massachusetts General Hospital, Harvard Medical School, Boston, United States of America

13Division of Nephrology and Center for Vascular Biology Research, Department, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, United States of America

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1Department of Neurosurgery, Massachusetts General Hospital, Harvard Medical School, Boston, United States of America

2Department of Neurosurgery, Yale University School of Medicine, New Haven, United States of America

3Section of Pulmonary, Critical Care, and Sleep Medicine, Department of Inte, Yale University School of Medicine, New Haven, United States of America

4Center for Genomic Medicine, Massachusetts General Hospital, Boston, United States of America

5Department of Pediatrics, Yale University School of Medicine, New Haven, United States of America

6Department of Neuroscience, University of Virginia School of Medicine, Charlottesville, United States of America

7Department of Genetics, School of Medicine, Washington University, St. Louis, United States of America

8Department of Neurosurgery, Barrow Neurological Institute, Phoenix, United States of America

9School of Pharmacy, University College London, London, United Kingdom

10Department of Genetics, Yale University School of Medicine, New Haven, United States of America

11Department of Molecular Biophysics and Biochemistry, Yale University, New Haven, United States of America

12Department of Neurology, Massachusetts General Hospital, Harvard Medical School, Boston, United States of America

13Division of Nephrology and Center for Vascular Biology Research, Department, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, United States of America

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Published September 10, 2026 - More info

J Clin Invest. https://doi.org/10.1172/JCI185791.
Copyright © 2026, Duy et al. This work is licensed under the Creative Commons Attribution 4.0 International License. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.
Published September 10, 2026 - Version history
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Abstract

Microglia play essential yet poorly understood roles in brain development, including axon guidance, regulation of neurogenesis, and pruning of neuronal projections. Congenital hydrocephalus (CH), characterized by enlarged cerebrospinal fluid (CSF)-filled ventricles, is a leading cause of pediatric brain surgery, but its molecular mechanisms remain unclear. We have identified what we believe to be novel, recurrent, damaging missense variants in the SH3-binding domain of the adaptor protein Growth Factor Receptor-Bound Protein 2 (GRB2) in unrelated patients with CH. GRB2 is significantly co-expressed with one of its known upstream receptor tyrosine kinase partners, CSF1R, in the developing human brain, particularly in a microglial subtype associated with regulation of neural stem cells. Immunoprecipitation validated GRB2-CSF1R binding in mouse microglial cells and human monocyte cell line. Cx3cr1-Grb2fl/fl mice engineered with conditional deletion of Grb2 in microglia exhibit congenital absence of microglia and early postnatal severe communicating (non-obstructive) hydrocephalus, mimicking GRB2-mutant patients. The severe ventriculomegaly of Cx3cr1-Grb2fl/fl mice is associated with both depletion of cerebral cortical neurons and impairment of glia-lymphatic-mediated CSF flow. Together, these findings implicate a role of GRB2 in microglia that could be essential for brain development and CSF homeostasis.

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