Mutations linked to loss of cell cycle control can render cells responsive to local differentiation cues.

Cell behaviors such as survival, proliferation, and death are governed by a multitude of cues, both intrinsic and extrinsic. To test whether a wild-type environment could encourage the survival and/or differentiation of neuronal progenitor cells with impaired cell cycle progression, we transplanted cells from cdk1, dtl, slbp, fbxo5, ahctf1, gins2, hdac1, mcm5, ssrp1a, and rbbp6 mutant zebrafish embryos into wild-type embryos, creating chimeric zebrafish with mutant cells in the developing eye. We found that when cells from cdk1, dtl, slbp, gins2, mcm5, or rbbp6 mutants were transplanted into wild-type hosts, survival and/or differentiation was almost always compromised in a manner consistent with cell-autonomous cell death. Interestingly, we observed that fbxo5, ahctf1, hdac1, or ssrp1a mutant cells survived and sometimes exhibited signs of differentiation when grafted into wild-type eyes.

Antagonism between Gdf6a and retinoic acid pathways controls timing of retinal neurogenesis and growth of the eye in zebrafish.

Maintaining neurogenesis in growing tissues requires a tight balance between progenitor cell proliferation and differentiation. In the zebrafish retina, neuronal differentiation proceeds in two stages with embryonic retinal progenitor cells (RPCs) of the central retina accounting for the first rounds of differentiation, and stem cells from the ciliary marginal zone (CMZ) being responsible for late neurogenesis and growth of the eye. In this study, we analyse two mutants with small eyes that display defects during both early and late phases of retinal neurogenesis. These mutants carry lesions in gdf6a, a gene encoding a BMP family member previously implicated in dorsoventral patterning of the eye. We show that gdf6a mutant eyes exhibit expanded retinoic acid (RA) signalling and demonstrate that exogenous activation of this pathway in wild-type eyes inhibits retinal growth, generating small eyes with a reduced CMZ and fewer proliferating progenitors, similar to gdf6a mutants. We provide evidence that RA regulates the timing of RPC differentiation by promoting cell cycle exit. Furthermore, reducing RA signalling in gdf6a mutants re-establishes appropriate timing of embryonic retinal neurogenesis and restores putative stem and progenitor cell populations in the CMZ. Together, our results support a model in which dorsally expressed gdf6a limits RA pathway activity to control the transition from proliferation to differentiation in the growing eye.