Gonadotropin-releasing hormone (GnRH) is secreted by neurons that migrate during development from the nasal placode to the hypothalamus along the axons of nasal neurons. GnRH deficiency causes reproductive disorders such as Kallmann syndrome (KS), which is characterised by delayed or absent puberty and no sense of smell. KS can be associated with mutations in SEMA3A (which encodes an axon guidance factor) and PLXNA1 (which encodes a SEMA3a co-receptor), two genes involved in patterning the axons along which GnRH neurons migrate. However, Plxna1-mutant mice have only mild GnRH deficiency. Now, Christiana Ruhrberg, Anna Cariboni and colleagues reveal that PLXNA1 acts redundantly with another plexin, PLXNA3, to pattern the axons that guide GnRH neurons. Using in situ hybridisation and immunostaining, the authors show that both Plxna1 and Plxna3 are expressed by nasal neurons. Furthermore, Plxna1/Plxna3 double mutants retain GnRH neurons in the nose, due to the mispatterned nasal axons at the brain boundary. PLXNA1/PLXNA3-deficient animals also have defective olfactory system development, consistent with symptoms in KS patients. Together, these data implicate both PLXNA1 and PLXNA3 in patterning the neurons along which GnRH neurons migrate, and highlight PLXNA3 as a candidate gene for KS.
