Journal
DEVELOPMENT
Volume 135, Issue 2, Pages 271-280Publisher
COMPANY OF BIOLOGISTS LTD
DOI: 10.1242/dev.009688
Keywords
eomesodermin; T-box transcription factors; pou4f2; retinal ganglion cells; optic nerve development; mouse
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Funding
- NCI NIH HHS [P30 CA008748, CA16672, P30 CA016672] Funding Source: Medline
- NEI NIH HHS [R01 EY013128, EY013128, EY010608-139005, EY11930, R01 EY011930] Funding Source: Medline
- NICHD NIH HHS [R01 HD052115, R01 HD052115-03, HD052115] Funding Source: Medline
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The mechanisms regulating retinal ganglion cell (RGC) development are crucial for retinogenesis and for the establishment of normal vision. However, these mechanisms are only vaguely understood. RGCs are the first neuronal lineage to segregate from pluripotent progenitors in the developing retina. As output neurons, RGCs display developmental features very distinct from those of the other retinal cell types. To better understand RGC development, we have previously constructed a gene regulatory network featuring a hierarchical cascade of transcription factors that ultimately controls the expression of downstream effector genes. This has revealed the existence of a Pou domain transcription factor, Pou4f2, that occupies a key node in the RGC gene regulatory network and that is essential for RGC differentiation. However, little is known about the genes that connect upstream regulatory genes, such as Pou4f2 with downstream effector genes responsible for RGC differentiation. The purpose of this study was to characterize the retinal function of eomesodermin (Eomes), a T-box transcription factor with previously unsuspected roles in retinogenesis. We show that Eomes is expressed in developing RGCs and is a mediator of Pou4f2 function. Pou4f2 directly regulates Eomes expression through a cis-regulatory element within a conserved retinal enhancer. Deleting Eomes in the developing retina causes defects reminiscent of those in Pou4f2(-/-) retinas. Moreover, myelin ensheathment in the optic nerves of Eomes(-/-) embryos is severely impaired, suggesting that Eomes regulates this process. We conclude that Eomes is a crucial regulator positioned immediately downstream of Pou4f2 and is required for RGC differentiation and optic nerve development.
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