JMJD-1.2/PHF8 controls axon guidance by regulating Hedgehog-like signaling

Abstract

Components of the KDM7 family of histone demethylases are implicated in neuronal development and one member, PHF8, is also found mutated in cases of X-linked mental retardation. However, how PHF8 regulates neurodevelopmental processes and contributes to the disease is still largely missing. Here we show that the catalytic activity of a PHF8 homolog in Caenorhabditis elegans, JMJD-1.2, is required non-cell autonomously for proper axon guidance. Loss of JMJD-1.2 deregulates the transcription of the Hedgehog-related genes wrt-8 and grl-16 whose overexpression is sufficient to induce the axonal defects. Deficiency of either wrt-8 or grl-16, or reduced expression of homologs of genes promoting Hedgehog signaling restore correct axon guidance in jmjd-1.2 mutant. Genetic and overexpression data indicate that Hedgehog-related genes act on axon guidance through actin remodelers. Thus, our study highlights a novel function of jmjd-1.2 in axon guidance that may be relevant for the onset of X-linked mental retardation and provides compelling evidences of a conserved function of the Hedgehog pathway in C. elegans axon migration.