AUTHOR=Hasegawa Sonoko , Kumagai Makiko , Hagihara Mitsue , Nishimaru Hiroshi , Hirano Keizo , Kaneko Ryosuke , Okayama Atsushi , Hirayama Teruyoshi , Sanbo Makoto , Hirabayashi Masumi , Watanabe Masahiko , Hirabayashi Takahiro , Yagi Takeshi 

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

JOURNAL=Frontiers in Molecular Neuroscience

VOLUME=9

YEAR=2016

URL=https://www.frontiersin.org/journals/molecular-neuroscience/articles/10.3389/fnmol.2016.00155

DOI=10.3389/fnmol.2016.00155

ISSN=1662-5099

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