Protocadherins mediate dendritic self-avoidance in the mammalian nervous system

Abstract

Dendritic arbors of many neurons are patterned by a process called self-avoidance, in which branches arising from a single neuron repel each other1-7. By minimizing gaps and overlaps within the arbor, self-avoidance facilitates complete coverage of a neuron’s territory by its neurites1-3. Remarkably, some neurons that display self-avoidance interact freely with other neurons of the same subtype, implying that they discriminate self from non-self. Here, we demonstrate roles for the clustered protocadherins (Pcdhs) in dendritic self-avoidance and self/non-self discrimination. The Pcdh locus encodes ~60 related cadherin-like transmembrane proteins, at least some of which exhibit isoform-specific homophilic adhesion in heterologous cells and are expressed stochastically and combinatorially in single neurons7-11. Deletion of all 22 Pcdhs in the mouse gamma subcluster (Pcdhgs) disrupts self-avoidance of dendrites in retinal starburst amacrine cells (SACs) and cerebellar Purkinje cells. Further genetic analysis of SACs showed that Pcdhgs act cell-autonomously during development, and that replacement of the 22 Pcdhgs with a single isoform restores self-avoidance. Moreover, expression of the same single isoform in all SACs decreases interactions among dendrites of neighboring SACs (heteroneuronal interactions). These results suggest that homophilic Pcdhg interactions between sibling neurites (isoneuronal interactions) generate a repulsive signal that leads to self-avoidance. In this model, heteroneuronal interactions are normally permitted because dendrites seldom encounter a matched set of Pcdhgs unless they emanate from the same soma. In many respects, our results mirror those reported for Dscam1 in Drosophila: this complex gene encodes thousands of recognition molecules that exhibit stochastic expression and isoform-specific interactions, and mediate both self-avoidance and self/non-self discrimination4-7,12-15. Thus, although insect Dscams and vertebrate Pcdhs share no sequence homology, they appear to underlie similar strategies for endowing neurons with distinct molecular identities and patterning their arbors.

Dendritic self-avoidance: protocadherins have it covered

“…The striking findings of Lefebvre et al [13] have supported this view by pinpointing a role for Pcdhs in self-recognition and self-avoidance in mammalian neurons. The authors focused on the Pcdh-γ cluster (Pcdhg), which was previously shown to be important for neuronal survival and synapse formation [14,15].…”

“…The authors focused on the Pcdh-γ cluster (Pcdhg), which was previously shown to be important for neuronal survival and synapse formation [14,15]. Mouse retinal starburst amacrine cells (SACs) express Pcdhg genes and display clear evidence of dendritic self-avoidance [13,14]. Using a pan-retina Cre driver to delete all 22 Pcdhg genes from all retinal cells, the authors observed increased SAC dendritic self-crossings and fasciculation ( Figure 1).…”

CTCF/cohesin-mediated DNA looping is required for protocadherin α promoter choice

“…This diversity appears to play a fundamental role in neural circuit assembly (22)(23)(24)(25). Understanding the mechanism by which this diversity is generated is, therefore, fundamental to understanding the development and function of the nervous system.…”

“…Recent studies have revealed a functional role for clustered Pcdh genes in dendritic development and self-avoidance [22][23][24][25]. Strikingly, a repertoire of heterozygous mutations in chromatid-segregating cohesin (SMC1A, SMC3, RAD21) and cohesin regulators (NIPBL, ESCO2) have been found to cause a class of developmental disorders known as Cornelia de Lange syndrome (CdLS) and Robert syndrome in humans (31).…”

Clustered protocadherins

“…These observations suggest that the role of the Pcdhg cluster in neuronal survival is primarily, if not entirely, mediated by one or more of the C-type isoforms, which are phylogenetically divergent among Pcdhs, and exhibit different expression patterns from the alternate isoforms. However, as the full cluster deletion mutants still die as neonates in the absence of apoptosis, the Pcdhg proteins must have an additional independent role that is essential for postnatal development, most likely in neural circuit assembly.Such a role was dramatically revealed in a detailed genetic study, where Pcdhg proteins were shown to mediate neurite self-avoidance in retinal starburst amacrine cells (SACs), as well as in cerebellar Purkinje cells (Lefebvre et al, 2012). Self-avoidance is a fundamental principle in neural circuit assembly, whereby sister axons and dendrites of the same neuron recognize and repel each other, while allowing multiple neurons to share the same receptive or projection field (Kramer and Kuwada, 1983).…”