JMJD-1.2/PHF8 controls axon guidance by regulating Hedgehog-like signaling [RESEARCH ARTICLE]

Alba Redo Riveiro, Luca Mariani, Emily Malmberg, Pier Giorgio Amendola, Juhani Peltonen, Garry Wong, and Anna Elisabetta Salcini

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.

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