Abstract
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.
Highlights
Construction of neural circuitry relies upon axons accomplishing several important developmental tasks
Retinal axons targeting the superior colliculus have enlarged termination zones in Phr1Δ8,9 mice, which suggests that Phr1 regulates axon termination in a subset of retinal ganglion cells [30]. These findings indicate that the PHR proteins are conserved regulators of axon termination, in the peripheral and central nervous system
Highwire and Regulator of Presynaptic Morphology 1 (RPM-1) are localized to the presynaptic terminal [6, 12, 13, 19], which is consistent with PHR proteins functioning in motor neurons to regulate synapse formation and function
Summary
Construction of neural circuitry relies upon axons accomplishing several important developmental tasks. Like Highwire, RPM-1 functions cell autonomously in motor neurons and mechanosensory neurons to regulate synapse formation. These findings from worms, flies, and mammals show that PHR proteins are conserved regulators of synapse formation in motor neurons.
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