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Abstract
Bone morphogenetic protein (BMP) signaling has emerged as an important regulator of sensory neuron development. Using a three-generation forward genetic screen in mice we have identified Megf8 as a novel modifier of BMP4 signaling in trigeminal ganglion (TG) neurons. Loss of Megf8 disrupts axon guidance in the peripheral nervous system and leads to defects in development of the limb, heart, and left-right patterning, defects that resemble those observed in Bmp4 loss-of-function mice. Bmp4 is expressed in a pattern that defines the permissive field for the peripheral projections of TG axons and mice lacking BMP signaling in sensory neurons exhibit TG axon defects that resemble those observed in Megf8 (-/-) embryos. Furthermore, TG axon growth is robustly inhibited by BMP4 and this inhibition is dependent on Megf8. Thus, our data suggest that Megf8 is involved in mediating BMP4 signaling and guidance of developing TG axons. DOI:http://dx.doi.org/10.7554/eLife.01160.001.
Highlights
During development, neurons of the peripheral nervous system (PNS) must project axons over long distances to form connections with their appropriate peripheral targets
Our findings demonstrate that loss of either BMP4 or multiple EGF-like-domains 8 (Megf8) leads to a similar spectrum of defects in the limb, left-right asymmetry, and heart, and that both BMP4 and Megf8 are required for normal development of the trigeminal ganglia (TG)
Megf8−/− explants exhibit significantly greater axon outgrowth in the presence of BMP4, but not under control culture conditions (Figure 6B,D). These results demonstrate that Megf8−/− axons are less sensitive to the inhibitory effects of BMP4 and that the response of TG neurons to BMP4 is partially dependent on Megf8 expression
Summary
Neurons of the peripheral nervous system (PNS) must project axons over long distances to form connections with their appropriate peripheral targets. To accomplish this task, axons of developing neurons rely on guidance provided by a variety of extracellular cues expressed in the surrounding environment and distal targets. Bone morphogenetic protein (BMP) signaling is an important regulator of sensory neuron development. BMP4 is expressed in the developing craniofacial region and signals retrogradely to coordinate differential gene expression and patterning along the dorsoventral axis of the trigeminal ganglion (Hodge et al, 2007). BMP4 appears to have a trophic effect on TG and DRG neurons as altering the level of BMP4 expression in the skin leads to changes in the peripheral innervation and number of sensory neurons found in both the TG and DRG (Guha et al, 2004)
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