title: Antagonism between Gdf6a and retinoic acid pathways controls timing of retinal neurogenesis and growth of the eye in zebrafish.
abstract: 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.
authors.affiliation: Department of Cell and Developmental Biology, UCL, Gower Street, London WC1E 6BT, UK.
authors.forename: Leonardo E
authors.initials: LE
authors.lastname: Valdivia
authors.affiliation: Department of Biology, Reed College, 3203 SE Woodstock Boulevard, Portland, OR 97202, USA.
authors.forename: Dayna B
authors.initials: DB
authors.lastname: Lamb
authors.affiliation: Department of Biology, Reed College, 3203 SE Woodstock Boulevard, Portland, OR 97202, USA.
authors.forename: Wilson
authors.initials: W
authors.lastname: Horner
authors.affiliation: Department of Cell and Developmental Biology, UCL, Gower Street, London WC1E 6BT, UK.
authors.forename: Claudia
authors.initials: C
authors.lastname: Wierzbicki
authors.affiliation: Department of Biology, Reed College, 3203 SE Woodstock Boulevard, Portland, OR 97202, USA.
authors.forename: Amanuel
authors.initials: A
authors.lastname: Tafessu
authors.affiliation: Department of Biology, Reed College, 3203 SE Woodstock Boulevard, Portland, OR 97202, USA.
authors.forename: Audrey M
authors.initials: AM
authors.lastname: Williams
authors.affiliation: Department of Cell and Developmental Biology, UCL, Gower Street, London WC1E 6BT, UK.
authors.forename: Gaia
authors.initials: G
authors.lastname: Gestri
authors.affiliation: Department of Cell and Developmental Biology, UCL, Gower Street, London WC1E 6BT, UK.
authors.forename: Anna M
authors.initials: AM
authors.lastname: Krasnow
authors.affiliation: Department of Biology, Reed College, 3203 SE Woodstock Boulevard, Portland, OR 97202, USA.
authors.forename: Terra S
authors.initials: TS
authors.lastname: Vleeshouwer-Neumann
authors.affiliation: Department of Biology, Reed College, 3203 SE Woodstock Boulevard, Portland, OR 97202, USA.
authors.forename: McKenzie
authors.initials: M
authors.lastname: Givens
authors.affiliation: Department of Cell and Developmental Biology, UCL, Gower Street, London WC1E 6BT, UK.
authors.forename: Rodrigo M
authors.initials: RM
authors.lastname: Young
authors.affiliation: Department of Cell and Developmental Biology, UCL, Gower Street, London WC1E 6BT, UK.
authors.forename: Lisa M
authors.initials: LM
authors.lastname: Lawrence
authors.affiliation: Department of Cell and Developmental Biology, UCL, Gower Street, London WC1E 6BT, UK.
authors.forename: Heather L
authors.initials: HL
authors.lastname: Stickney
authors.affiliation: Department of Cell and Developmental Biology, UCL, Gower Street, London WC1E 6BT, UK.
authors.forename: Thomas A
authors.initials: TA
authors.lastname: Hawkins
authors.affiliation: Department of Cell and Developmental Biology, UCL, Gower Street, London WC1E 6BT, UK.
authors.forename: Quenten P
authors.initials: QP
authors.lastname: Schwarz
authors.affiliation: Department of Cell and Developmental Biology, UCL, Gower Street, London WC1E 6BT, UK.
authors.forename: Florencia
authors.initials: F
authors.lastname: Cavodeassi
authors.affiliation: Department of Cell and Developmental Biology, UCL, Gower Street, London WC1E 6BT, UK s.wilson@ucl.ac.uk cervenyk@reed.edu.
authors.forename: Stephen W
authors.initials: SW
authors.lastname: Wilson
authors.affiliation: Department of Cell and Developmental Biology, UCL, Gower Street, London WC1E 6BT, UK Department of Biology, Reed College, 3203 SE Woodstock Boulevard, Portland, OR 97202, USA s.wilson@ucl.ac.uk cervenyk@reed.edu.
authors.forename: Kara L
authors.initials: KL
authors.lastname: Cerveny
mesh_terms: D000818:Animals; D019485:Bone Morphogenetic Proteins / Q000378:metabolism; D002453:Cell Cycle / Q000235:genetics; D049109:Cell Proliferation; D004625:Embryo, Nonmammalian / Q000196:embryology; D055431:Growth Differentiation Factor 6 / Q000235:genetics*; D055495:Neurogenesis / Q000235:genetics* / Q000502:physiology; D012160:Retina / Q000196:embryology*; D015398:Signal Transduction / Q000235:genetics; D013234:Stem Cells / Q000166:cytology; D014212:Tretinoin / Q000378:metabolism*; D015027:Zebrafish / Q000196:embryology*; D029961:Zebrafish Proteins / Q000235:genetics*
chemical_list: D019485:Bone Morphogenetic Proteins; D055431:Growth Differentiation Factor 6; D029961:Zebrafish Proteins; C420987:gdf6a protein, zebrafish; D014212:Tretinoin
keywords: BMP; Ciliary marginal zone; Gdf6a; Neurogenesis; Retinal stem cells; Retinoic acid; Zebrafish