Distinct and Cooperative Functions for the Protocadherin-α, -β and -γ Clusters in Neuronal Survival and Axon Targeting

Abstract

The clustered <i>protocadherin</i> (<i>Pcdh</i>) genes are divided into the <i>Pcdh</i>α<i>, Pcdh</i>β, and <i>Pcdh</i>γ clusters. Gene-disruption analyses in mice have revealed the <i>in vivo</i> functions of the <i>Pcdh</i>α and <i>Pcdh</i>γ clusters. However, all Pcdh protein isoforms form combinatorial <i>cis</i>-hetero dimers and enter <i>trans</i>-homophilic interactions. Here we addressed distinct and cooperative functions in the <i>Pcdh</i> clusters by generating six cluster-deletion mutants (Δα, Δβ, Δγ, Δ<i>αβ</i>, Δ<i>βγ</i>, and Δ<i>αβγ</i>) and comparing their phenotypes: Δα, Δβ, and Δ<i>αβ</i> mutants were viable and fertile; Δγ mutants lived less than 12 h; and Δ<i>βγ</i> and Δ<i>αβγ</i> mutants died shortly after birth. The <i>Pcdh</i>α<i>, Pcdh</i>β, and <i>Pcdh</i>γ clusters were individually and cooperatively important in olfactory-axon targeting and spinal-cord neuron survival. Neurodegeneration was most severe in Δ<i>αβγ</i> mutants, indicating that <i>Pcdh</i>α and <i>Pcdh</i>β function cooperatively for neuronal survival. The <i>Pcdh</i>α<i>, Pcdh</i>β, and <i>Pcdh</i>γ clusters share roles in olfactory-axon targeting and neuronal survival, although to different degrees.