Dataset Information

DSCAM promotes self-avoidance in the developing mouse retina by masking the functions of cadherin superfamily members.

ABSTRACT: During neural development, self-avoidance ensures that a neuron's processes arborize to evenly fill a particular spatial domain. At the individual cell level, self-avoidance is promoted by genes encoding cell-surface molecules capable of generating thousands of diverse isoforms, such as Dscam1 (Down syndrome cell adhesion molecule 1) in Drosophila Isoform choice differs between neighboring cells, allowing neurons to distinguish "self" from "nonself". In the mouse retina, Dscam promotes self-avoidance at the level of cell types, but without extreme isoform diversity. Therefore, we hypothesize that DSCAM is a general self-avoidance cue that "masks" other cell type-specific adhesion systems to prevent overly exuberant adhesion. Here, we provide in vivo and in vitro evidence that DSCAM masks the functions of members of the cadherin superfamily, supporting this hypothesis. Thus, unlike the isoform-rich molecules tasked with self-avoidance at the individual cell level, here the diversity resides on the adhesive side, positioning DSCAM as a generalized modulator of cell adhesion during neural development.

SUBMITTER: Garrett AM

PROVIDER: S-EPMC6205498 | biostudies-literature | 2018 Oct

REPOSITORIES: biostudies-literature

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DSCAM promotes self-avoidance in the developing mouse retina by masking the functions of cadherin superfamily members.

Garrett Andrew M AM Khalil Andre A Walton David O DO Burgess Robert W RW

Proceedings of the National Academy of Sciences of the United States of America 20181008 43

During neural development, self-avoidance ensures that a neuron's processes arborize to evenly fill a particular spatial domain. At the individual cell level, self-avoidance is promoted by genes encoding cell-surface molecules capable of generating thousands of diverse isoforms, such as Dscam1 (Down syndrome cell adhesion molecule 1) in Drosophila Isoform choice differs between neighboring cells, allowing neurons to distinguish "self" from "nonself". In the mouse retina, Dscam</ ...[more]

PMID: 30297418

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Project description:BackgroundOrgans are programmed to acquire a particular size during development, but the regulatory mechanisms that dictate when dividing progenitor cells should permanently exit the cell cycle and stop producing additional daughter cells are poorly understood. In differentiated tissues, tumor suppressor genes maintain a constant cell number and intact tissue architecture by controlling proliferation, apoptosis and cell dispersal. Here we report a similar role for two tumor suppressor genes, the Zac1 zinc finger transcription factor and that encoding the cytokine TGFbetaII, in the developing retina.ResultsUsing loss and gain-of-function approaches, we show that Zac1 is an essential negative regulator of retinal size. Zac1 mutants develop hypercellular retinae due to increased progenitor cell proliferation and reduced apoptosis at late developmental stages. Consequently, supernumerary rod photoreceptors and amacrine cells are generated, the latter of which form an ectopic cellular layer, while other retinal cells are present in their normal number and location. Strikingly, Zac1 functions as a direct negative regulator of a rod fate, while acting cell non-autonomously to modulate amacrine cell number. We implicate TGFbetaII, another tumor suppressor and cytokine, as a Zac1-dependent amacrine cell negative feedback signal. TGFbetaII and phospho-Smad2/3, its downstream effector, are expressed at reduced levels in Zac1 mutant retinae, and exogenous TGFbetaII relieves the mutant amacrine cell phenotype. Moreover, treatment of wild-type retinae with a soluble TGFbeta inhibitor and TGFbeta receptor II (TGFbetaRII) conditional mutants generate excess amacrine cells, phenocopying the Zac1 mutant phenotype.ConclusionWe show here that Zac1 has an essential role in cell number control during retinal development, akin to its role in tumor surveillance in mature tissues. Furthermore, we demonstrate that Zac1 employs a novel cell non-autonomous strategy to regulate amacrine cell number, acting in cooperation with a second tumor suppressor gene, TGFbetaII, through a negative feedback pathway. This raises the intriguing possibility that tumorigenicity may also be associated with the loss of feedback inhibition in mature tissues.

Dataset Information

DSCAM promotes self-avoidance in the developing mouse retina by masking the functions of cadherin superfamily members.

Publications

DSCAM promotes self-avoidance in the developing mouse retina by masking the functions of cadherin superfamily members.

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