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Regulation of neural circuit formation by protocadherins

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Abstract

The protocadherins (Pcdhs), which make up the most diverse group within the cadherin superfamily, were first discovered in the early 1990s. Data implicating the Pcdhs, including ~60 proteins encoded by the tandem Pcdha, Pcdhb, and Pcdhg gene clusters and another ~10 non-clustered Pcdhs, in the regulation of neural development have continually accumulated, with a significant expansion of the field over the past decade. Here, we review the many roles played by clustered and non-clustered Pcdhs in multiple steps important for the formation and function of neural circuits, including dendrite arborization, axon outgrowth and targeting, synaptogenesis, and synapse elimination. We further discuss studies implicating mutation or epigenetic dysregulation of Pcdh genes in a variety of human neurodevelopmental and neurological disorders. With recent structural modeling of Pcdh proteins, the prospects for uncovering molecular mechanisms of Pcdh extracellular and intracellular interactions, and their role in normal and disrupted neural circuit formation, are bright.

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Abbreviations

Pcdhs:

Protocadherins

EC:

Extracellular cadherin

PP1a:

Protein phosphatase 1a

P:

Postnatal day

WIRS:

WRC interacting receptor sequence

WRC:

WAVE regulatory complex

FAK:

Focal adhesion kinase

PKC:

Protein kinase C

SACs:

Starburst amacrine cells

LTP:

Long-term potentiation

Mdm2:

Murine double minute 2

EFMR:

Epilepsy and mental retardation limited to females

FIRES:

Febrile infection-related epilepsy syndromes

ASDs:

Autistic spectrum disorders

RTT:

Rett syndrome

MECP2 :

Methyl-CpG-binding protein 2

ADHD:

Attention deficit hyperactivity disorder

DS:

Down syndrome

FASDs:

Fetal alcohol spectrum disorders

HD:

Huntington’s disease

mHtt :

Mutant huntingtin gene

GWAS:

Genome-wide association studies

SCZ:

Schizophrenia

BPD:

Bipolar disorder

MDD:

Major depressive disorder

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Acknowledgements

Work in the Weiner Laboratory described herein has been supported by the following Grants to J.A.W.: R01 NS055272 and R21 NS090030.

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Peek, S., Mah, K.M. & Weiner, J.A. Regulation of neural circuit formation by protocadherins. Cell. Mol. Life Sci. 74, 4133–4157 (2017). https://doi.org/10.1007/s00018-017-2572-3

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