Multicluster Pcdh Diversity is Required for Mouse Olfactory Neural Circuit Assembly

Overview

Journal Science

Specialty Science

Date 2017 Apr 29

PMID 28450637

Citations 81

Authors

George Mountoufaris

Weisheng V Chen

Yusuke Hirabayashi

Sean OKeeffe

Maxime Chevee

Chiamaka L Nwakeze

Franck Polleux

Tom Maniatis

Affiliations

Soon will be listed here.

Abstract

The vertebrate clustered protocadherin (Pcdh) cell surface proteins are encoded by three closely linked gene clusters (α, β, and γ). Here, we show that all three gene clusters functionally cooperate to provide individual mouse olfactory sensory neurons (OSNs) with the cell surface diversity required for their assembly into distinct glomeruli in the olfactory bulb. Although deletion of individual clusters had subtle phenotypic consequences, the loss of all three clusters (tricluster deletion) led to a severe axonal arborization defect and loss of self-avoidance. By contrast, when endogenous Pcdh diversity is overridden by the expression of a single-tricluster gene repertoire (α and β and γ), OSN axons fail to converge to form glomeruli, likely owing to contact-mediated repulsion between axons expressing identical combinations of Pcdh isoforms.

Citing Articles

Role of FPR2 antagonism in alleviating social isolation-induced depression and protecting blood-brain barrier integrity.

Zheng J, Wang H, Wu W, Wang L, Qin M, Zhu L J Neuroinflammation. 2025; 22(1):79.

PMID: 40083006 PMC: 11907847. DOI: 10.1186/s12974-025-03408-4.

Nervous system-wide analysis of all cadherins reveals neuron-specific functions across multiple anatomical scales.

Majeed M, Liao C, Hobert O Sci Adv. 2025; 11(8):eads2852.

PMID: 39983000 PMC: 11844738. DOI: 10.1126/sciadv.ads2852.

Structural insights into the in situ assembly of clustered protocadherin γB4.

Zhang Z, Chen F, Zhang Z, Guo L, Feng T, Fang Z Nat Commun. 2025; 16(1):1682.

PMID: 39956828 PMC: 11830823. DOI: 10.1038/s41467-025-56948-x.

A New Targeted Transgenic Mouse Line for the Study of Protocadherin γC4.

McLeod C, Hanes C, Fuller L, Bhandari S, Lanthier H, Burgess R Genesis. 2025; 63(1):e70010.

PMID: 39923243 PMC: 11810047. DOI: 10.1002/dvg.70010.

Mitotic block and epigenetic repression underlie neurodevelopmental defects and neurobehavioral deficits in congenital heart disease.

Gabriel G, Yagi H, Tan T, Bais A, Glennon B, Stapleton M Nat Commun. 2025; 16(1):469.

PMID: 39774941 PMC: 11707140. DOI: 10.1038/s41467-024-55741-6.

References

Esumi S, Kakazu N, Taguchi Y, Hirayama T, Sasaki A, Hirabayashi T . Monoallelic yet combinatorial expression of variable exons of the protocadherin-alpha gene cluster in single neurons. Nat Genet. 2005; 37(2):171-6. DOI: 10.1038/ng1500. View

Chen W, Alvarez F, Lefebvre J, Friedman B, Nwakeze C, Geiman E . Functional significance of isoform diversification in the protocadherin gamma gene cluster. Neuron. 2012; 75(3):402-9. PMC: 3426296. DOI: 10.1016/j.neuron.2012.06.039. View

Hasegawa S, Hamada S, Kumode Y, Esumi S, Katori S, Fukuda E . The protocadherin-alpha family is involved in axonal coalescence of olfactory sensory neurons into glomeruli of the olfactory bulb in mouse. Mol Cell Neurosci. 2008; 38(1):66-79. DOI: 10.1016/j.mcn.2008.01.016. View

Saraiva L, Ibarra-Soria X, Khan M, Omura M, Scialdone A, Mombaerts P . Hierarchical deconstruction of mouse olfactory sensory neurons: from whole mucosa to single-cell RNA-seq. Sci Rep. 2015; 5:18178. PMC: 4680959. DOI: 10.1038/srep18178. View

Rubinstein R, Aye Thu C, Goodman K, Wolcott H, Bahna F, Mannepalli S . Molecular logic of neuronal self-recognition through protocadherin domain interactions. Cell. 2015; 163(3):629-42. PMC: 4624033. DOI: 10.1016/j.cell.2015.09.026. View

Buck L, Axel R . A novel multigene family may encode odorant receptors: a molecular basis for odor recognition. Cell. 1991; 65(1):175-87. DOI: 10.1016/0092-8674(91)90418-x. View

Lefebvre J, Kostadinov D, Chen W, Maniatis T, Sanes J . Protocadherins mediate dendritic self-avoidance in the mammalian nervous system. Nature. 2012; 488(7412):517-21. PMC: 3427422. DOI: 10.1038/nature11305. View

Chess A, Simon I, Cedar H, Axel R . Allelic inactivation regulates olfactory receptor gene expression. Cell. 1994; 78(5):823-34. DOI: 10.1016/s0092-8674(94)90562-2. View

Mountoufaris G, Chen W, Hirabayashi Y, OKeeffe S, Chevee M, Nwakeze C . Multicluster Pcdh diversity is required for mouse olfactory neural circuit assembly. Science. 2017; 356(6336):411-414. PMC: 5529182. DOI: 10.1126/science.aai8801. View

10.

Hummel T, Vasconcelos M, Clemens J, Fishilevich Y, Vosshall L, Zipursky S . Axonal targeting of olfactory receptor neurons in Drosophila is controlled by Dscam. Neuron. 2003; 37(2):221-31. DOI: 10.1016/s0896-6273(02)01183-2. View

11.

Hattori D, Demir E, Kim H, Viragh E, Zipursky S, Dickson B . Dscam diversity is essential for neuronal wiring and self-recognition. Nature. 2007; 449(7159):223-7. PMC: 2691715. DOI: 10.1038/nature06099. View

12.

Schreiner D, Weiner J . Combinatorial homophilic interaction between gamma-protocadherin multimers greatly expands the molecular diversity of cell adhesion. Proc Natl Acad Sci U S A. 2010; 107(33):14893-8. PMC: 2930437. DOI: 10.1073/pnas.1004526107. View

13.

Mombaerts P, Wang F, Dulac C, CHAO S, Nemes A, Mendelsohn M . Visualizing an olfactory sensory map. Cell. 1996; 87(4):675-86. DOI: 10.1016/s0092-8674(00)81387-2. View

14.

Garrett A, Schreiner D, Lobas M, Weiner J . γ-protocadherins control cortical dendrite arborization by regulating the activity of a FAK/PKC/MARCKS signaling pathway. Neuron. 2012; 74(2):269-76. PMC: 3582349. DOI: 10.1016/j.neuron.2012.01.028. View

15.

Lefebvre J, Zhang Y, Meister M, Wang X, Sanes J . gamma-Protocadherins regulate neuronal survival but are dispensable for circuit formation in retina. Development. 2008; 135(24):4141-51. PMC: 2644426. DOI: 10.1242/dev.027912. View

16.

Chen W, Maniatis T . Clustered protocadherins. Development. 2013; 140(16):3297-302. PMC: 3737714. DOI: 10.1242/dev.090621. View

17.

Wang X, Su H, Bradley A . Molecular mechanisms governing Pcdh-gamma gene expression: evidence for a multiple promoter and cis-alternative splicing model. Genes Dev. 2002; 16(15):1890-905. PMC: 186422. DOI: 10.1101/gad.1004802. View

18.

Hasegawa S, Hirabayashi T, Kondo T, Inoue K, Esumi S, Okayama A . Constitutively expressed Protocadherin-α regulates the coalescence and elimination of homotypic olfactory axons through its cytoplasmic region. Front Mol Neurosci. 2012; 5:97. PMC: 3472330. DOI: 10.3389/fnmol.2012.00097. View

19.

Wang X, Weiner J, Levi S, Craig A, Bradley A, Sanes J . Gamma protocadherins are required for survival of spinal interneurons. Neuron. 2002; 36(5):843-54. DOI: 10.1016/s0896-6273(02)01090-5. View

20.

Aye Thu C, Chen W, Rubinstein R, Chevee M, Wolcott H, Felsovalyi K . Single-cell identity generated by combinatorial homophilic interactions between α, β, and γ protocadherins. Cell. 2014; 158(5):1045-1059. PMC: 4183217. DOI: 10.1016/j.cell.2014.07.012. View