PLXNA3

PLXNA3 encodes plexin-A3, a receptor for semaphorin-3F (SEMA3F) that functions in the guidance of GnRH neurons and olfactory/vomeronasal nerve fibers during human fetal development (PMID:33495532). PLXNA3 is expressed along the olfactory nerve and the intracranial projection of the vomeronasal/terminal nerve, and together with PLXNA1 and PLXNA2 is present in early migratory GnRH neurons, positioning it within the SEMA3F signaling pathway that directs these cells (PMID:33495532). Loss-of-function missense variants in PLXNA3 cause idiopathic hypogonadotropic hypogonadism, consistent with disrupted SEMA3F-mediated guidance of GnRH neurons and olfactory/vomeronasal fibers (PMID:33495532). Beyond this receptor role and disease association, no further mechanistic detail — including downstream signaling, co-receptor requirements, or structural basis of ligand binding — has been characterized in the available corpus.

1. 2021 Medium

   Established that PLXNA3 is a disease gene for idiopathic hypogonadotropic hypogonadism and placed it mechanistically in the SEMA3F guidance pathway for GnRH neurons and olfactory/vomeronasal nerve fibers.

   Evidence Exome sequencing of 216 IHH patients with cell-based functional assays of variants in HEK293T cells and fluorescent immunohistochemistry of human fetal nasal/forebrain tissue

   PMID:33495532

   Open questions at the time

   • No reconstitution of SEMA3F binding or downstream signaling by PLXNA3 reported
   • No structural data on the receptor or its variants
   • Relative contributions of PLXNA1/A2/A3 to GnRH neuron guidance not dissected

• How PLXNA3 transduces SEMA3F signaling at the molecular level and which co-receptors and downstream effectors mediate GnRH neuron and nerve fiber guidance remains unresolved.
• Downstream signaling effectors unidentified
• Co-receptor (e.g. neuropilin) requirements not tested in this corpus
• In vivo guidance mechanism not directly demonstrated