Gamma Protocadherins Are Required for Survival of Spinal Interneurons

Wang, Xiaozhong; Weiner, Joshua A.; Lévi, Sabine; Craig, Ann Marie; Bradley, Allan; Sanes, Joshua R.

doi:10.1016/s0896-6273(02)01090-5

Cited by 264 publications

(493 citation statements)

References 48 publications

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“…17). The number of synapses in the gray matter of the spinal cord was decreased in these mice, consistent with the idea that ␥-Pcdhs are required for synaptic development.…”

supporting

confidence: 85%

“…Mice lacking the entire 22-gene Pcdh-␥ locus (Pcdh-␥ del/del ; ref. 17) and mice lacking Bax (23,24) have been described. Both were maintained on a C57͞B6 background.…”

Section: Methodsmentioning

confidence: 99%

“…Antibodies used (and their sources) were: anti-NeuN (Chemicon); anti-gephyrin and anti-glycine receptor (Alexis, San Diego); anti-microtubule-associated protein 2 (MAP2, Sigma); anti-class III ␤-tubulin (TuJ1, Covance, Princeton, NJ); antiglutamic acid decarboxylase (GAD, Developmental Studies Hybridoma Bank, Iowa City, IA); anti-vesicular glutamate transporter (VGlut) 1 and 2 (mixed 1:1 and used together, Chemicon); anti-postsynaptic density (PSD)-95 (Affinity Bioreagents, Golden, CO); anti-synaptophysin (Zymed); anti-cleaved caspase-3 (Cell Signaling Technology, Beverly, MA); antineurofilaments (Sternberger-Meyer, Jarrettsville, MD); rabbit anti-GFP (Chemicon); and a rabbit antiserum to the common Pcdh-␥ C-terminal exons (17). Neuro Trace 435 (Molecular Probes) was used as a fluorescent Nissl stain.…”

Section: Methodsmentioning

confidence: 99%

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Gamma protocadherins are required for synaptic development in the spinal cord

Weiner

Wang

Tapia

et al. 2004

Proc. Natl. Acad. Sci. U.S.A.

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212

265

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Fifty-eight cadherin-related protocadherin (Pcdh) genes are tandemly arrayed in three clusters (␣, ␤, and ␥) 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-␥ cluster have decreased numbers of spinal cord synapses and are nearly immobile. Interpretation of this phenotype was complicated, however, by the fact that Pcdh-␥ loss also led to apoptosis of many spinal interneurons. Here, we used two methods to circumvent apoptosis and neurodegeneration in Pcdh-␥ mutant mice. First, we analyzed mutants lacking both Pcdh-␥ proteins and the proapoptotic protein Bax. Second, we generated a hypomorphic allele of Pcdh-␥ 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 ␥-Pcdhs in synaptic development and establish genetic tools for elucidating their contribution to synaptic specificity.A s synapses form, their presynaptic and postsynaptic elements become linked by transmembrane adhesion molecules, including members of the Ig and cadherin superfamilies. Some of these adhesion molecules, such as SynCAM, neuroligin, and neurexin, might function primarily to coordinate presynaptic and postsynaptic differentiation, whereas others might contribute to the selectivity with which synaptic connections form between appropriate partners (reviewed in refs. 1-4). The diversity of the Ig and cadherin families and the binding specificities of individual members suggests that they might be involved in both aspects of synaptogenesis. Support for roles in synaptic specificity has recently been obtained for at least five Ig superfamily members, Sidekick-1 and-2 in vertebrates (5), Syg-1 and -2 in worms (6, 7), and DS-CAM in flies (8, 9).Additional attractive candidate synaptic recognition molecules are the nearly 60 cadherin-related protocadherin (Pcdh) genes tandemly arrayed in three clusters on a single chromosome in mammals (10, 11). These clusters, termed Pcdh-␣, -␤, and -␥, each contain multiple ''variable'' exons encoding the extracellular, transmembrane, and proximal cytoplasmic domains of individual isoforms. Within the Pcdh-␣ and -␥ clusters, each variable exon is transcribed from its own promoter and spliced to ''constant'' exons that encode a shared C-terminal domain (12-15). Many neuronal populations express multiple Pcdh genes, and the ␣-and ␥-Pcdh proteins are concentrated at, although not exclusively localized to, synapses (16-19). Together, these features have led to the hypothesis that combinatorial patterns of Pcdh expression promote specific interactions between presynaptic and ...

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“…17). The number of synapses in the gray matter of the spinal cord was decreased in these mice, consistent with the idea that ␥-Pcdhs are required for synaptic development.…”

supporting

confidence: 85%

“…Mice lacking the entire 22-gene Pcdh-␥ locus (Pcdh-␥ del/del ; ref. 17) and mice lacking Bax (23,24) have been described. Both were maintained on a C57͞B6 background.…”

Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

See 1 more Smart Citation

Gamma protocadherins are required for synaptic development in the spinal cord

Weiner

Wang

Tapia

et al. 2004

Proc. Natl. Acad. Sci. U.S.A.

Self Cite

212

265

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“…Hence, Flamingo/Celsr may have a conserved function in preventing axonal and synaptic degeneration in fruit flies and mammals. Such a neuroprotective function for Flamingo is also shared by another atypical cadherin family in mammals, which have also been shown to be critically required for the survival of spinal motoneurons (Wang et al, 2002) and for synaptogenesis (Weiner et al, 2005). Therefore, atypical cadherins have emerged as a unique class of molecules important for multiple neuronal functions, including axonal growth and targeting, synapse formation, maintenance of the health of axons and synapses.…”

Section: Flamingo Helps Prevent Axonal Degeneration and Synapse Lossmentioning

confidence: 99%

The atypical cadherin flamingo regulates synaptogenesis and helps prevent axonal and synaptic degeneration in Drosophila

Bao

Berlanga

Xue

et al. 2007

Molecular and Cellular Neuroscience

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The formation of synaptic connections with target cells and maintenance of axons are highly regulated and crucial for neuronal function. The atypical cadherin and G-protein-coupled receptor Flamingo and its orthologs in amphibians and mammals have been shown to regulate cell polarity, dendritic and axonal growth, and neural tube closure. However, the role of Flamingo in synapse formation and function and in axonal health remains poorly understood. Here we show that fmi mutations cause a significant increase in the number of ectopic synapses on muscles and result in the formation of novel en passant synapses along axons, and unique presynaptic varicosities, including active zones, within axons. fmi mutations also cause defective synaptic responses in a small subset of muscles, an agedependent loss of muscle innervation and a drastic degeneration of axons in 3 rd instar larvae without an apparent loss of neurons. Neuronal expression of Flamingo rescues all of these synaptic and axonal defects and larval lethality. Based on these observations, we propose that Flamingo is required in neurons for synaptic target selection, synaptogenesis, the survival of axons and synapses, and adult viability. These findings shed new light on a possible role for Flamingo in progressive neurodegenerative diseases.

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“…The protocadherin gene family has almost 60 members clustered in three tandem arrays. Previous work in mice lacking one of these clusters had produced a nearly immobile animal with reduced spinal cord synapses (23). However, the phenotype also produced apoptosis of the same neurons, complicating the interpretation.…”

Section: A Different Washingtonmentioning

confidence: 99%

Biography of Joshua R. Sanes

Davis¹

2004

Proc. Natl. Acad. Sci. U.S.A.

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Gamma Protocadherins Are Required for Survival of Spinal Interneurons

Cited by 264 publications

References 48 publications

Gamma protocadherins are required for synaptic development in the spinal cord

Gamma protocadherins are required for synaptic development in the spinal cord

The atypical cadherin flamingo regulates synaptogenesis and helps prevent axonal and synaptic degeneration in Drosophila

Biography of Joshua R. Sanes

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