Exploring the role of neuronal individuality in neuronal survival and brain function

 

Abstract

In the brain, individual neurons form precise and complex neural networks that underlie a wide range of brain functions, including cognition, emotion, motor control, and the formation of massive memories. Recent studies have revealed that each neuron possesses distinct molecular, structural, and functional identities. However, the fundamental question of how such individuality arises and how it contributes to the organization of brain functions and behavioral control remains unresolved. Our previous work identified the clustered protocadherin (cPcdh) gene family as key molecules that generate neuronal individuality by producing random yet combinatorial gene expression patterns (Morishita & Yagi, Curr Opin Cell Biol, 2007). These molecules have been implicated in neuronal survival, dendritic and axonal self-recognition, circuit formation, and behavioral regulation. Despite these insights, the functional significance of the stochastic expression of cPcdh genes remains incompletely understood. Here we aim to elucidate the molecular mechanisms by which randomly expressed cPcdh genes regulate neuronal survival and synapse formation. Furthermore, by capturing and manipulating the stochastic expression of cPcdh, we investigate how neuronal individuality contributes to the establishment of complex and precise neural networks and the formation of higher-order brain functions.

 

Ref.

1. Kohmura N, Senzaki K, Hamada S, Kai N, Yasuda R, Watanabe M, Ishii H, Yasuda M, Mishina M, Yagi T: Diversity revealed by anovel family of cadherins expressed in neurons at synaptic complex. Neuron 20, 1137-1151, 1998.
2. Esumi S, Kakazu N, Taguchi Y, Hirayama T, Sasaki A, Hirabayashi T, Koide T, Kitsukawa T, Hamada S, Yagi T: Monoallelic yet combinatorial expression of variable exons of the CNR/Protocadherin-a gene cluster in single neurons. Nature Genet 37, 171-176, 2005.
3. Morishita H, Yagi T: Protocadherin family: diversity, structure, and function. Curr Opin Cell Biol 19, 584-592, 2007.
4. Hirayama T, Tarusawa E, Yoshimura Y, Galjart N, Yagi T: CTCF is required for neural development and stochastic expression of clustered Pcdh genes in neurons. Cell Rep 2, 345-357, 2012.
5. Toyoda S, Kawaguchi M, Kobayashi T, Tarusawa E, Toyama T, Okano M, Oda M, Nakauchi H, Yoshimura Y, Sanbo M, Hirabayashi M, Hirayama T, Hirabayashi T, Yagi T: Developmental epigenetic modification regulates stochastic expression of clustered Protocadherin genes, generating single neuron diversity. Neuron 82, 94-108, 2014.
6. Kobayashi H, Takemoto K, Sanbo M, Hirabayashi M, Hirabayashi T, Hirayama T, Kiyonari H, Abe T, Yagi T: Isoform requirement of clustered protocadherin for preventing neuronal apoptosis and neonatal lethality. iScience 26, 105766, 2022.
7. Hoshino N, Kanadome T, Takasugi T, Itoh M, Kaneko R, Inoue YU,Inoue T, Hirabayashi T, Watanabe M, Matsuda T, Nagai T, Tarusawa E, Yagi T: Visualization of trans homophilic interaction of clustered protocadherin in neurons, Proc Natl Acad Sci USA 120 (38), e2301003120, 2023.