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Conditional Gata2 inactivation results in HSC loss and lymphatic mispatterning
Kim-Chew Lim, … , Masayuki Yamamoto, James Douglas Engel
Kim-Chew Lim, … , Masayuki Yamamoto, James Douglas Engel
Published September 10, 2012
Citation Information: J Clin Invest. 2012;122(10):3705-3717. https://doi.org/10.1172/JCI61619.
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Research Article Article has an altmetric score of 20

Conditional Gata2 inactivation results in HSC loss and lymphatic mispatterning

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Abstract

The transcription factor GATA-2 plays vital roles in quite diverse developmental programs, including hematopoietic stem cell (HSC) survival and proliferation. We previously identified a vascular endothelial (VE) enhancer that regulates GATA-2 activity in pan-endothelial cells. To more thoroughly define the in vivo regulatory properties of this enhancer, we generated a tamoxifen-inducible Cre transgenic mouse line using the Gata2 VE enhancer (Gata2 VECre) and utilized it to temporally direct tissue-specific conditional loss of Gata2. Here, we report that Gata2 VECre–mediated loss of GATA-2 led to anemia, hemorrhage, and eventual death in edematous embryos. We further determined that the etiology of anemia in conditional Gata2 mutant embryos involved HSC loss in the fetal liver, as demonstrated by in vitro colony-forming and immunophenotypic as well as in vivo long-term competitive repopulation experiments. We further documented that the edema and hemorrhage in conditional Gata2 mutant embryos were due to defective lymphatic development. Thus, we unexpectedly discovered that in addition to its contribution to endothelial cell development, the VE enhancer also regulates GATA-2 expression in definitive fetal liver and adult BM HSCs, and that GATA-2 function is required for proper lymphatic vascular development during embryogenesis.

Authors

Kim-Chew Lim, Tomonori Hosoya, William Brandt, Chia-Jui Ku, Sakie Hosoya-Ohmura, Sally A. Camper, Masayuki Yamamoto, James Douglas Engel

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Figure 9

Aberrant lymphatic development in TgVE:Gata2–/fl embryos.

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Aberrant lymphatic development in TgVE:Gata2–/fl embryos.
 
(A and B) Tx...
(A and B) Tx-treated E14.5 Gata2+/fl (A) and TgVE:Gata2–/fl (B) embryos were fixed in 4% paraformaldehyde and then gradually cleared in benzyl benzoate:benzyl alcohol for whole-mount photography. Note the blood-engorged jugulo-axillary lymph sac (arrow) in the TgVE:Gata2–/fl, but in not in the control, embryo. (C–F) Transverse paraffin sections (6 μM) of an E13.5 Tx-treated (E9–E11) TgVE:Gata2+/+ (C and E) or TgVE:Gata2–/fl (D and F–J) embryos were stained with H&E. While in the control embryo, the jugular vein (v) is distinctly separated from the jugular lymph sac (ls) at the axial level of the thyroid gland (th, C; an enlarged view of boxed area is shown in E), only a single vessel lumen is observed in the Tx-treated TgVE:Gata2–/fl embryo (D; enlarged view of boxed area is shown in F). C and D were taken at the same magnification; the tissue edema in TgVE:Gata2–/fl embryo did not permit coverage of the entire area in the microscopic field. By following serial sections anteriorly (G and H) and posteriorly (I and J) of the section shown in F, it appeared that the jugular vein remained abnormally connected to the lymphatic system. Note the interstitial edema (indicated by the arrow; B) and the aberrant presence of erythrocytes in the lymph sacs (indicated by asterisks) before the onset of visible hemorrhage (e.g., see Figure 8) of E13.5 Tx-treated TgVE:Gata2–/fl embryo. a, carotid artery; eo, esophagus; sg, sympathetic ganglion; tr, trachea; va, vagal nerve trunk. Scale bars: 1 mm (A and B), 200 μm (C and D), 100 μm (E–J).

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ISSN: 0021-9738 (print), 1558-8238 (online)

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