| Description |
During development, all seven of the major retinal cell types are produced in a distinct yet overlapping order from a single pool of multipotent retinal progenitor cells (RPCs). In order to accomplish this task, it is thought that each individual RPC proceeds irreversibly through a series of intrinsically defined competence states, capable of producing only a subset of these cell types at any given time. To ensure that all early- and late-born cell types are produced in the correct number, RPCs must not only proceed through these competence states in a timely fashion, but also limit their rate of differentiation in order to prevent premature depletion. Lhx2 is a LIM-homeobox transcription factor expressed in many different tissues during development, known to regulate both proliferation and fate choice. It is also expressed in most if not all RPCs, and we assessed its contribution to their various properties by performing conditional inactivation at multiple time points during retinal neurogenesis. We find that Lhx2 is required within a limited temporal window to ensure the balanced production of earlyborn cell types, as retinal ganglion cells (RGCs) are selectively overproduced in the Lhx2 conditional knock-out (CKO) retina. LHX2 is also necessary for the normal cessation of RGC genesis, suggesting that in its absence, RPCs fail to undergo a normal transition in competence. We show that sustained Notch signaling, dependent on the transcription factor Rbpj, is likely responsible for maintaining a low level of both proliferation and neurogenesis in the absence of Lhx2, based on their successive requirements at distinct stages in the lineage progression of RPCs. We find further that LHX2 is required for the iv normal response of RPCs to Sonic Hedgehog (SHH), a negative-feedback signal secreted by RGCs and known to limit their further generation. In addition, we show that both LHX2 and SHH promote the expression of Ascl1, a gene expressed in RPCs and implicated as molecular readout of competence progression. Together, the results presented here demonstrate how intrinsic factors such as LHX2 may perform distinct functions at distinct phases of RPC lineage progression to orchestrate the process of retinal neurogenesis. |
