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First published online 11 September 2008
doi: 10.1242/dev.024612

Development 135, 3379-3388 (2008)
Published by The Company of Biologists 2008
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Rewiring the retinal ganglion cell gene regulatory network: Neurod1 promotes retinal ganglion cell fate in the absence of Math5

Chai-An Mao1, Steven W. Wang2, Ping Pan1 and William H. Klein1,3,*

1 Department of Biochemistry and Molecular Biology, The University of Texas M. D. Anderson Cancer Center, Houston, TX 77030, USA.
2 Department of Ophthalmology and Visual Science, The University of Texas Houston Medical School, Houston, TX 77030, USA.
3 Training Program in Genes and Development, The University of Texas Graduate School of Biomedical Sciences at Houston, Houston, TX 77030, USA.

* Author for correspondence (e-mail: whklein{at}mdanderson.org)

Accepted 26 August 2008

Retinal progenitor cells (RPCs) express basic helix-loop-helix (bHLH) factors in a strikingly mosaic spatiotemporal pattern, which is thought to contribute to the establishment of individual retinal cell identity. Here, we ask whether this tightly regulated pattern is essential for the orderly differentiation of the early retinal cell types and whether different bHLH genes have distinct functions that are adapted for each RPC. To address these issues, we replaced one bHLH gene with another. Math5 is a bHLH gene that is essential for establishing retinal ganglion cell (RGC) fate. We analyzed the retinas of mice in which Math5 was replaced with Neurod1 or Math3, bHLH genes that are expressed in another RPC and are required to establish amacrine cell fate. In the absence of Math5, Math5Neurod1-KI was able to specify RGCs, activate RGC genes and restore the optic nerve, although not as effectively as Math5. By contrast, Math5Math3-KI was much less effective than Math5Neurod1-KI in replacing Math5. In addition, expression of Neurod1 and Math3 from the Math5Neurod1-KI/Math3-KI allele did not result in enhanced amacrine cell production. These results were unexpected because they indicated that bHLH genes, which are currently thought to have evolved highly specialized functions, are nonetheless able to adjust their functions by interpreting the local positional information that is programmed into the RPC lineages. We conclude that, although Neurod1 and Math3 have evolved specialized functions for establishing amacrine cell fate, they are nevertheless capable of alternative functions when expressed in foreign environments.

Key words: Retinal ganglion cells, Retinal progenitor cells, bHLH genes, Math5 (Atoh7), Neurod1, Math3 (Neurod4)






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