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 often found to be mutated in cases of X-linked mental retardation. However, how PHF8 regulates neurodevelopmental processes and contributes to the disease is still largely unknown. Here, we show that the catalytic activity of a PHF8 homolog in, JMJD-1.2, is required non-cell-autonomously for proper axon guidance. Loss of JMJD-1.2 dysregulates transcription of the Hedgehog-related genesand, the overexpression of which is sufficient to induce the axonal defects. Deficiency of eitheror, or reduced expression of homologs of genes promoting Hedgehog signaling, restores correct axon guidance inmutants. Genetic and overexpression data indicate that Hedgehog-related genes act on axon guidance through actin remodelers. Thus, our study highlights a novel function ofin axon guidance that might be relevant for the onset of X-linked mental retardation and provides compelling evidence of a conserved function of the Hedgehog pathway inaxon migration.