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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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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DOI: https://doi.org/10.1007/s00018-017-2572-3