Involvement of Mash1 in EGF-Mediated Regulation of Differentiation in the Vertebrate Retina

Abstract

It is believed that signaling through the epidermal growth factor (EGF) receptor plays a critical role in the development of Drosophila eyes. In the present study we have analyzed the role that EGF-mediated signaling plays in vertebrate retinal development. We have observed that during late retinal neurogenesis EGF delays rod photoreceptor differentiation and that this effect of EGF involves the modulation of expression of a homologue of Drosophila proneural genes, Mash1. EGF causes a significant decrease in Mash1 expression and an increase in the proportion of proliferating cells in the retina in vitro. The decrease in Mash1 expression is accompanied by a concomitant decrease in opsin expression, a marker for overt rod photoreceptor differentiation. Withdrawal of EGF leads to an increase in both Mash1 and opsin expression; however, the onset of expression of Mash1 precedes that of opsin. Our study identifies a proliferative intermediate precursor, characterized by Mash1 expression, that is the target of EGF-mediated suppression of rod photoreceptor differentiation. Based on the evolutionarily conserved roles of EGF- and Notch-mediated signaling in the delay of differentiation in proliferating precursors we propose that these distinct signaling mechanisms act in concert to ensure the fidelity of the strict temporal and spatial nature of cell fate determination in the retina.

Maintenance of retinal stem cells by Abcg2 is regulated by notch signaling

“…The NSP, besides containing post mitotic cells, includes proliferating precursors in different stages of differentiation. The developing retina contains committed precursors characterized by their ability to divide and expression of proneural genes, such as Mash1 (Ahmad et al, 1998). These precursors are malleable and when exposed to conditions that promote the maintenance of retinal stem cells rather than their differentiation they revert to a progenitor stage (Ahmad et al, 1998).…”

“…Next, to determine the mechanism underlying the expansion of SP cell populations in response to the ectopic expression of Abcg2, we examined the expression of Mash1, a proneural gene, whose transient expression characterizes the proliferating intermediate retinal precursors during late retinal histogenesis (Ahmad et al, 1998). Levels of Mash1 transcripts along with those corresponding to cell cycle regulators, cyclin D1, P27 kip1 and Ki67, and the pan neuronal marker, Map2, were determined in SP and NSP cells in E18 neurospheres transduced with G1-Abcg2 or empty retrovirus.…”

Mammalian Scratch: A neural-specific Snail family transcriptional repressor

“…2 F and G). This laminar domain of mScrt expression was absent from the VZ of the retina, which resides next to the retinal pigment epithelium and is comprised mostly of mitotically active cells (19). Throughout the CNS, mScrt expression persisted into postnatal life.…”

Mammalian Neural Stem-Cell Renewal: Nature versus Nurture

“…Interestingly, a link between the FGF family and the Notch pathway was recently observed in neuroepithelial cells (80) (55) and suggest that FGF-2 stimulates stem-cell expansion (symmetric division) through the activation of the Notch pathway. EGF probably acts in a similar fashion (although this has not been confirmed) because ectopic EGF stimulation on retinal explant expand eye neuroepithelial cells (12,29,81), and prevents cell differentiation (or prolong the non-differentiated state) (29). The maintenance of precursor proliferation by epigenetic stimulation through the activation of the Notch pathway is also documented for cerebellar granule neuron precursors stimulated by sonic hedgehog (Shh) (59).…”

“…Similar results also seem to be intrinsic to the developing retina (29), but long-term studies and subcloning are necessary to reveal the characteristics of these cells. Interestingly, mouse CNS stem cells, including those of the spinal cord, can also be isolated in the presence of FGF-2 (17,(30)(31)(32).…”