Gamma protocadherins are required for synaptic development in the spinal cord

Joshua A Weiner; Xiaozhong Wang; Juan Carlos Tapia; Joshua R Sanes

doi:10.1073/pnas.0407931101

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Gamma protocadherins are required for synaptic development in the spinal cord

Journal article

Open access

Peer reviewed

Gamma protocadherins are required for synaptic development in the spinal cord

Joshua A Weiner, Xiaozhong Wang, Juan Carlos Tapia and Joshua R Sanes

Proceedings of the National Academy of Sciences - PNAS, Vol.102(1), pp.8-14

01/04/2005

DOI: 10.1073/pnas.0407931101

PMCID: PMC544073

PMID: 15574493

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Abstract

Fifty-eight cadherin-related protocadherin (Pcdh) genes are tandemly arrayed in three clusters (alpha, beta, and gamma) on mouse chromosome 18. The large number of clustered Pcdh family members, their presence at synapses, and the known binding specificities of other cadherin superfamily members all suggest that these Pcdhs play roles in specifying synaptic connectivity. Consistent with this idea, mice lacking all 22 genes of the Pcdh-gamma cluster have decreased numbers of spinal cord synapses and are nearly immobile. Interpretation of this phenotype was complicated, however, by the fact that Pcdh-gamma loss also led to apoptosis of many spinal interneurons. Here, we used two methods to circumvent apoptosis and neurodegeneration in Pcdh-gamma mutant mice. First, we analyzed mutants lacking both Pcdh-gamma proteins and the proapoptotic protein Bax. Second, we generated a hypomorphic allele of Pcdh-gamma in which apoptosis was minimal. In both cases, spinal interneurons were preserved but the mice bore dramatically decreased numbers of spinal cord synapses and exhibited profound neurological defects. Moreover, synaptic function was compromised in neurons cultured from the hypomorphs. These results provide evidence for a direct role of gamma-Pcdhs in synaptic development and establish genetic tools for elucidating their contribution to synaptic specificity.

Electrophysiology

Mutation

Neurons - pathology

Spinal Cord - metabolism

Cadherins - metabolism

Synapses - pathology

bcl-2-Associated X Protein

Proto-Oncogene Proteins c-bcl-2 - metabolism

Spinal Cord - embryology

Patch-Clamp Techniques

Animals

Synapses - metabolism

Mice

Neurons - metabolism

Cadherins - genetics

Proto-Oncogene Proteins c-bcl-2 - genetics

Organ Culture Techniques

Details

Title: Subtitle: Gamma protocadherins are required for synaptic development in the spinal cord
Creators: Joshua A Weiner - Department of Anatomy and Neurobiology, Washington University Medical School, 660 South Euclid Avenue, St. Louis, MO 63110, USA
Xiaozhong Wang
Juan Carlos Tapia
Joshua R Sanes
Resource Type: Journal article
Publication Details: Proceedings of the National Academy of Sciences - PNAS, Vol.102(1), pp.8-14
DOI: 10.1073/pnas.0407931101
PMID: 15574493
PMCID: PMC544073
NLM abbreviation: Proc Natl Acad Sci U S A
ISSN: 0027-8424
eISSN: 1091-6490
Publisher: National Academy of Sciences; United States
Language: English
Date published: 01/04/2005
Academic Unit: Liberal Arts and Science Admin; Psychiatry; Iowa Neuroscience Institute; Biology
Record Identifier: 9983997437502771

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