title: Id2a functions to limit Notch pathway activity and thereby influence the transition from proliferation to differentiation of retinoblasts during zebrafish retinogenesis.
abstract: During vertebrate retinogenesis, the precise balance between retinoblast proliferation and differentiation is spatially and temporally regulated through a number of intrinsic factors and extrinsic signaling pathways. Moreover, there are complex gene regulatory network interactions between these intrinsic factors and extrinsic pathways, which ultimately function to determine when retinoblasts exit the cell cycle and terminally differentiate. We recently uncovered a cell non-autonomous role for the intrinsic HLH factor, Id2a, in regulating retinoblast proliferation and differentiation, with Id2a-deficient retinae containing an abundance of proliferative retinoblasts and an absence of terminally differentiated retinal neurons and glia. Here, we report that Id2a function is necessary and sufficient to limit Notch pathway activity during retinogenesis. Id2a-deficient retinae possess elevated levels of Notch pathway component gene expression, while retinae overexpressing id2a possess reduced expression of Notch pathway component genes. Attenuation of Notch signaling activity by DAPT or by morpholino knockdown of Notch1a is sufficient to rescue both the proliferative and differentiation defects in Id2a-deficient retinae. In addition to regulating Notch pathway activity, through a novel RNA-Seq and differential gene expression analysis of Id2a-deficient retinae, we identify a number of additional intrinsic and extrinsic regulatory pathway components whose expression is regulated by Id2a. These data highlight the integral role played by Id2a in the gene regulatory network governing the transition from retinoblast proliferation to terminal differentiation during vertebrate retinogenesis.
authors.affiliation: Section of Molecular Cell and Developmental Biology, The University of Texas at Austin, Austin, TX 78712, USA.
authors.forename: Rosa A
authors.initials: RA
authors.lastname: Uribe
authors.forename: Taejoon
authors.initials: T
authors.lastname: Kwon
authors.forename: Edward M
authors.initials: EM
authors.lastname: Marcotte
authors.forename: Jeffrey M
authors.initials: JM
authors.lastname: Gross
mesh_terms: D000818:Animals; D002454:Cell Differentiation; D049109:Cell Proliferation; D018507:Gene Expression Regulation, Developmental; D053263:Gene Regulatory Networks; D018398:Homeodomain Proteins / Q000235:genetics / Q000378:metabolism*; D051797:Inhibitor of Differentiation Protein 2 / Q000235:genetics* / Q000378:metabolism; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism*; D051881:Receptor, Notch1 / Q000235:genetics / Q000378:metabolism*; D012160:Retina / Q000166:cytology* / Q000196:embryology* / Q000378:metabolism; D015398:Signal Transduction; D015027:Zebrafish; D029961:Zebrafish Proteins / Q000235:genetics* / Q000378:metabolism
chemical_list: D018398:Homeodomain Proteins; C577676:Id2a protein, zebrafish; D051797:Inhibitor of Differentiation Protein 2; D009419:Nerve Tissue Proteins; D051881:Receptor, Notch1; D029961:Zebrafish Proteins; C437805:notch1a protein, zebrafish