The PHR proteins: intracellular signaling hubs in neuronal development and axon degeneration

During development, a coordinated and integrated series of events must be accomplished in order to generate
functional neural circuits. Axons must navigate toward target cells, build synaptic connections, and terminate
outgrowth. The PHR proteins (consisting of mammalian Phr1/MYCBP2, Drosophila Highwire and C. elegans RPM-1)
function in each of these events in development. Here, we review PHR function across species, as well as the
myriad of signaling pathways PHR proteins regulate. These findings collectively suggest that the PHR proteins are
intracellular signaling hubs, a concept we explore in depth. Consistent with prominent developmental functions,
genetic links have begun to emerge between PHR signaling networks and neurodevelopmental disorders, such as
autism, schizophrenia and intellectual disability. Finally, we discuss the recent and important finding that PHR
proteins regulate axon degeneration, which has further heightened interest in this fascinating group of molecules.