We have performed a three-generation, forward genetic screen to identify recessive mutations that affect the patterning of the peripheral nervous system. Using this assay, we identified Sema3A(K108N), a novel loss-of-function allele of Sema3A. Class 3 semaphorins, which include Sema3A, are structurally conserved secreted proteins that play critical roles in the development and function of the nervous system. Sema3A(K108N) mutant mice phenocopy Sema3A-null mice, and Sema3A(K108N) protein fails to repel or collapse DRG axons in vitro. K108 is conserved among semaphorins, yet the loss-of-function effects associated with K108N are not the result of impaired expression, secretion, or binding of Sema3A to its high-affinity receptor Neuropilin-1 (Npn-1). Using in silico modeling and mutagenesis of other semaphorin family members, we predict that Sema3A(K108N) interacts poorly with the Npn-1/PlexA holoreceptor and, thus, interferes with its ability to signal at the growth cone. Therefore, through the use of a forward-genetic screen we have identified a novel allele of Sema3A that provides structural insight into the mechanism of Sema3A/Npn-1/PlexinA signaling.
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