Tfap2a and 2b act downstream of Ptf1a to promote amacrine cell differentiation during retinogenesis

Jin, Kangxin; Jiang, Hongzhi; Xiao, Dongchang; Zou, Min; Zhu, Jun; Xiang, Mengqing

doi:10.1186/s13041-015-0118-x

Cited by 65 publications

(76 citation statements)

References 60 publications

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“…Because tfap2a and tfap2b function redundantly in the development of other tissues, we next determined whether these two factors acted similarly in the pronephros (Knight et al, 2005;Van Otterloo et al, 2018;Seberg et al, 2017;Bassett et al, 2012;Jin et al, 2015). To interrogate this, we performed combination knockdown and mutant studies, and assayed expression of the solute transporters that characterize the distal nephron segments at 24 hpf.…”

Section: Resultsmentioning

confidence: 99%

Tfap2a is a novel gatekeeper of nephron differentiation during kidney development

et al. 2019

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Renal functional units known as nephrons undergo patterning events during development that create a segmental array of cellular compartments with discrete physiological identities. Here, from a forward genetic screen using zebrafish, we report the discovery that transcription factor AP-2 alpha (tfap2a) coordinates a gene regulatory network that activates the terminal differentiation program of distal segments in the pronephros. We found that tfap2a acts downstream of Iroquois homeobox 3b (irx3b), a distal lineage transcription factor, to operate a circuit consisting of tfap2b, irx1a and genes encoding solute transporters that dictate the specialized metabolic functions of distal nephron segments. Interestingly, this regulatory node is distinct from other checkpoints of differentiation, such as polarity establishment and ciliogenesis. Thus, our studies reveal insights into the genetic control of differentiation, where tfap2a is essential for regulating a suite of segment transporter traits at the final tier of zebrafish pronephros ontogeny. These findings have relevance for understanding renal birth defects, as well as efforts to recapitulate nephrogenesis in vivo to facilitate drug discovery and regenerative therapies.

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Section: Resultsmentioning

confidence: 99%

Tfap2a is a novel gatekeeper of nephron differentiation during kidney development

et al. 2019

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“…Foxn4 acts in early-stage RPCs in conjunction with Rorb to activate expression of Ptf1a, which functions upstream of Tfap2a/b to drive amacrine cell specification (Jin et al, 2015; Liu et al, 2013). Downstream of these events, other factors act to control the specification of amacrine cell subtype.…”

Section: Discussionmentioning

confidence: 99%

Pax6 is essential for the generation of late-born retinal neurons and for inhibition of photoreceptor-fate during late stages of retinogenesis

Remez

Onishi

Menuchin-Lasowski

et al. 2017

Developmental Biology

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In the developing retina, as in other regions of the CNS, neural progenitors give rise to individual cell types during discrete temporal windows. Pax6 is expressed in retinal progenitor cells (RPCs) throughout the course of retinogenesis, and has been shown to be required during early retinogenesis for generation of most early-born cell types. In this study, we examined the function of Pax6 in postnatal mouse retinal development. We found that Pax6 is essential for the generation of late-born interneurons, while inhibiting photoreceptor differentiation. Generation of bipolar interneurons requires Pax6 expression in RPCs, while Pax6 is required for the generation of glycinergic, but not for GABAergic or non-GABAergic-non-glycinergic (nGnG) amacrine cell subtypes. In contrast, overexpression of either full-length Pax6 or its 5a isoform in RPCs induces formation of cells with nGnG amacrine features, and suppresses generation of other inner retinal cell types. Moreover, overexpression of both Pax6 variants prevents photoreceptor differentiation, most likely by inhibiting Crx expression. Taken together, these data show that Pax6 acts in RPCs to control differentiation of multiple late-born neuronal cell types.

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“…Around E8, AP-2a is expressed in the INL, shown both in this study and by others, 33 and has been implicated in HC and AC differentiation downstream of Ptf1a. 25,34 Moreover, FoxN4 has also been suggested to regulate the generation of ACs and HCs by acting upstream of Ptf1a. [35][36][37] Strikingly, our results show that in the dsMab21l2-electroporated retina, AP-2a is severely reduced, with only a few remaining AP-2aþ cells.…”

Section: Discussionmentioning

confidence: 99%

“…6Q). AP-2a is also implicated in AC specification, 25 and was expressed in the INL in the control E8 retina (Fig. 6M).…”

Section: Gcl and Inl Patterning Is Disturbed After Mab21l2 Downregulamentioning

confidence: 99%

Temporal Requirement ofMab21l2During Eye Development in Chick Reveals Stage-Dependent Functions for Retinogenesis

Sghari

Gunhaga

2018

Invest. Ophthalmol. Vis. Sci.

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PURPOSE. Different missense mutations in the single exon gene Mab21l2 have been identified in unrelated families with various bilateral eye malformations, including microphthalmia, anophthalmia, and coloboma, but the molecular function of Mab21l2 during eye development still remains largely unknown. METHODS.We have established an in vivo Mab21l2-deficient eye development model in chick, by using a Mab21l2 RNA interference construct that we electroporated in ovo in prospective retinal cells. In addition, we designed a Mab21l2 gain-of-function electroporation vector. Mab21l2-modulated retinas were analyzed on consecutive sections in terms of morphology, and molecular markers for apoptosis, cell proliferation, and retinogenesis.RESULTS. Our Mab21l2-deficient chick model mimics human ocular phenotypes. When Mab21l2 is downregulated prior to optic vesicle formation, the embryos develop anophthalmia, and Mab21l2 inhibition by optic cup stages results in a microphthalmic colobomatous phenotype. Our results show that inhibition of Mab21l2 affects cell proliferation, cell cycle exit, and the expression of Atoh7/Ath5, NeuroD4/Ath3, Isl1, Pax6, AP-2a, and Prox1. In addition, Mab21l2 overexpression hampers cell cycle exit and differentiation of retinal progenitor cells (RPCs). CONCLUSIONS.Our results highlight the importance of a regulated temporal expression of Mab21l2 during eye development: At early stages, Mab21l2 is required to maintain RPC proliferation and expansion of cell number; before retinogenesis, a decrease in Mab21l2 expression in proliferating RPCs is required for cell cycle exit and differentiation; during retinogenesis, Mab21l2 is chronologically upregulated in RGCs, followed by differentiated horizontal and amacrine cells and cone photoreceptor cells.

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Tfap2a and 2b act downstream of Ptf1a to promote amacrine cell differentiation during retinogenesis

Cited by 65 publications

References 60 publications

Tfap2a is a novel gatekeeper of nephron differentiation during kidney development

Tfap2a is a novel gatekeeper of nephron differentiation during kidney development

Pax6 is essential for the generation of late-born retinal neurons and for inhibition of photoreceptor-fate during late stages of retinogenesis

Temporal Requirement ofMab21l2During Eye Development in Chick Reveals Stage-Dependent Functions for Retinogenesis

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