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Combinatorial effects of Alpha- and Gamma-Protocadherins on neuronal survival and dendritic self-avoidance

Ing-Esteves, S; Kostadinov, D; Marocha, J; Sing, AD; Joseph, KS; Laboulaye, M; Sanes, JR; (2018) Combinatorial effects of Alpha- and Gamma-Protocadherins on neuronal survival and dendritic self-avoidance. Journal of Neuroscience 10.1523/JNEUROSCI.3035-17.2018. Green open access

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Abstract

The clustered Protocadherins (Pcdhs) comprise 58 cadherin-related proteins encoded by three tandemly-arrayed gene clusters, Pcdh-alpha, -beta, and --gamma (Pcdha, Pcdhb, Pcdhg). Pcdh isoforms from different clusters are combinatorially expressed in neurons. They form multimers that interact homophilically, and mediate a variety of developmental processes, including neuronal survival, synaptic maintenance, axonal tiling and dendritic self-avoidance. Most studies have analyzed clusters individually. Here, we assess functional interactions between Pcdha and Pcdhg clusters. To circumvent neonatal lethality associated with deletion of Pcdhgs, we used Crispr-Cas9 genome editing in mice to combine a constitutive Pcdha mutant allele with a conditional Pcdhg allele. We analyzed roles of Pcdhas and Pcdhgs in the retina and cerebellum from mice (both sexes) lacking one or both clusters. In retina, Pcdhgs are essential for survival of inner retinal neurons and dendrite self-avoidance of starburst amacrine cells, while Pcdhas are dispensable for both processes. Deletion of both Pcdha and Pcdhg clusters led to far more dramatic defects in survival and self-avoidance than Pcdhg deletion alone. Comparisons of an allelic series of mutants support the conclusion that Pcdhas and Pcdhgs function together in a dose-dependent and cell-type specific manner to provide a critical threshold of Pcdh activity. In the cerebellum, Pcdhas and Pcdhgs also act synergistically to mediate self-avoidance of Purkinje cell dendrites, with modest but significant defects in either single mutant and dramatic defects in the double mutant. Together, our results demonstrate complex patterns of redundancy between Pcdh clusters and the importance of Pcdh cluster diversity in postnatal CNS development.

Type: Article
Title: Combinatorial effects of Alpha- and Gamma-Protocadherins on neuronal survival and dendritic self-avoidance
Location: United States
Open access status: An open access version is available from UCL Discovery
DOI: 10.1523/JNEUROSCI.3035-17.2018
Publisher version: https://doi.org/10.1523/JNEUROSCI.3035-17.2018
Language: English
Additional information: This version is the version of record. For information on re-use, please refer to the publisher’s terms and conditions.
UCL classification: UCL
UCL > Provost and Vice Provost Offices
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences > Div of Medicine
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences > Div of Medicine > Wolfson Inst for Biomedical Research
URI: https://discovery.ucl.ac.uk/id/eprint/10044901
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