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

Valdivia, L.E., Lamb, D.B., Horner, W., Wierzbicki, C., Tafessu, A., Williams, A.M., Gestri, G., Krasnow, A.M., Vleeshouwer-Neumann, T.S., Givens, M., Young, R.M., Lawrence, L.M., Stickney, H.L., Hawkins, T.A., Schwarz, Q.P., Cavodeassi, F., Wilson, S.W., Cerveny, K.L.
Development (Cambridge, England)   143(7): 1087-98 (Journal)
Registered Authors
Cavodeassi, Florencia, Cerveny, Kara, Gestri, Gaia, Hawkins, Tom, Krasnow, Anna, Stickney, Heather, Valdivia, Leonardo, Wierzbicki, Claudia, Wilson, Steve, Young, Rodrigo
Retinoic acid, BMP, Gdf6a, Ciliary marginal zone, Neurogenesis, Retinal stem cells, Zebrafish
MeSH Terms
  • Animals
  • Bone Morphogenetic Proteins/metabolism
  • Cell Cycle/genetics
  • Cell Proliferation
  • Embryo, Nonmammalian/embryology
  • Growth Differentiation Factor 6/genetics*
  • Neurogenesis/genetics*
  • Neurogenesis/physiology
  • Retina/embryology*
  • Signal Transduction/genetics
  • Stem Cells/cytology
  • Tretinoin/metabolism*
  • Zebrafish/embryology*
  • Zebrafish Proteins/genetics*
26893342 Full text @ Development
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 both during 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 by which dorsally expressed gdf6a limits RA pathway activity to control the transition from proliferation toward differentiation in the growing eye.
Genes / Markers
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Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Engineered Foreign Genes