The role of Math5 in retinal development.

摘要

The neural retina contains seven major cell types that derive from a common pool of multipotential progenitors. To choose a fate (determination), a progenitor must exit the cell cycle, acquire competence, specify a cell fate, and differentiate. During embryonic development retinal progenitors express the transcription factor Math5. When Math5 function is removed in mice, progenitors fail to adopt retinal ganglion cell (RGC) fate. In this dissertation, I have tested the cell-autonomous role of Math5 in RGC fate determination. I have also evaluated the effects of RGC agenesis on visual system development and physiology, light dependent behavior and the retinal vasculature.; The suprachiasmatic nuclei (SCN) regulate circadian behavior. To test how RGCs influence SCN function, circadian behavior was examined in Math5-null mice which lack RGCs and optic nerves. These mutants had free-running behavioral rhythms with normal periods that did not entrain to light stimuli. Thus, the lack of RGCs does not affect the intrinsic rhythmicity of the SCN. To evaluate the effects of RGC agenesis on retinal electrophysiology, corneal flash electroretinograms (ERG) were recorded. Math5 mutants have diminished waveform amplitudes only, indicating that RGC responses do not significantly contribute to ERG waveforms.; RGCs are thought to regulate the development of retinal astrocytes, which directly induce retinal vascularization. Math5-null mice were used to test how RGCs affect retinal vascular and astrocyte development. The mutants have major astrocyte defects, resulting in the failure of normal retinal blood vessel growth, persistence of the fetal vasculature, and abnormal neovascularization later in development.; To control RGC fate determination, Math5 may act instructively, irreversibly specifying competent progenitor cells to become RGCs. Conversely, Math5 may act permissively, establishing RGC competence within progenitors, only some of which will be specified as RGCs. To test these mechanisms, I conducted a lineage analysis to trace the fate of Math5+ progenitors. These progenitors contributed to all seven retinal cell types, indicating that Math5 acts permissively. Moreover, Math5 expression was confined to postmitotic cells. Thus, a subpopulation of progenitors exits the cell cycle, express Math5, and become competent to form RGCs. These results suggest that competence is progressively restricted as the retina develops.