Nuclear factor I-A regulates diverse reactive astrocyte responses after CNS injury
Dylan Laug, … , Hyun Kyoung Lee, Benjamin Deneen
Dylan Laug, … , Hyun Kyoung Lee, Benjamin Deneen
Published September 9, 2019
Citation Information: J Clin Invest. 2019;129(10):4408-4418. https://doi.org/10.1172/JCI127492.
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Research Article Development Neuroscience

Nuclear factor I-A regulates diverse reactive astrocyte responses after CNS injury

Abstract

Reactive astrocytes are associated with every form of neurological injury. Despite their ubiquity, the molecular mechanisms controlling their production and diverse functions remain poorly defined. Because many features of astrocyte development are recapitulated in reactive astrocytes, we investigated the role of nuclear factor I-A (NFIA), a key transcriptional regulator of astrocyte development whose contributions to reactive astrocytes remain undefined. Here, we show that NFIA is highly expressed in reactive astrocytes in human neurological injury and identify unique roles across distinct injury states and regions of the CNS. In the spinal cord, after white matter injury (WMI), NFIA-deficient astrocytes exhibit defects in blood-brain barrier remodeling, which are correlated with the suppression of timely remyelination. In the cortex, after ischemic stroke, NFIA is required for the production of reactive astrocytes from the subventricular zone (SVZ). Mechanistically, NFIA directly regulates the expression of thrombospondin 4 (Thbs4) in the SVZ, revealing a key transcriptional node regulating reactive astrogenesis. Together, these studies uncover critical roles for NFIA in reactive astrocytes and illustrate how region- and injury-specific factors dictate the spectrum of reactive astrocyte responses.

Authors

Dylan Laug, Teng-Wei Huang, Navish A. Bosquez Huerta, Anna Yu-Szu Huang, Debosmita Sardar, Joshua Ortiz-Guzman, Jeffrey C. Carlson, Benjamin R. Arenkiel, Chay T. Kuo, Carrie A. Mohila, Stacey M. Glasgow, Hyun Kyoung Lee, Benjamin Deneen

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Figure 5

Selective deletion of NFIA in the SVZ impairs reactive astrocyte production after ischemia.

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Selective deletion of NFIA in the SVZ impairs reactive astrocyte product...
(A–C) NFIA was expressed in proliferating BrdU+ populations in the SVZ at 5 dpi, and genetic deletion of NFIA with GFAP-CreER resulted in decreased proliferation, as measured by BrdU incorporation into SVZ cell populations (D–F). (G) Quantification of BrdU+ cells within the SVZ after injury in control and NFIAfl/fl GFAP-CreER mice. Quantification was derived from 5 control and 4 experimental animals and 8 sections per animal. *P = 0.0016, student’s t test. (H) Experimental timeline for Cre virus–mediated deletion of NFIA from SVZ progenitor cells and subsequent photothrombotic stroke and analysis. (I–L) Control experiments showing SVZ-derived, tdTomato-labeled cell populations (I), NFIA expression (J), and generated reactive astrocytes residing at the injury site (K and L). (M–P) Deletion of NFIA from SVZ cell populations resulted in decreased numbers of tdTomato+ cells (M) and reduced expression of NFIA (N) and GFAP (O and P) at the injury site. (Q) Quantification of tdTomato+ cells at the injury border in NFIAfl/+ Rosa-tdTomato and NFIAfl/fl Rosa-tdTomato mice. Quantification was derived from 8 sections per animal and 3 animals per genotype. *P < 0.05 and **P = 0.0065, by Student’s t test. Data are shown as box-and-whisker plots. The bounds of the boxes represent upper and lower quartiles, the lines in the boxes represent the median, and the whiskers represent the maximum and minimal values. Scale bars: 100 μm (A–F) and 15 μm (I–P). CC, corpus callosum; LV, lateral ventricle.