Dysfunctional SEMA3E signaling underlies gonadotropin-releasing hormone neuron deficiency in Kallmann syndrome

J Clin Invest. 2015 Jun;125(6):2413-28. doi: 10.1172/JCI78448. Epub 2015 May 18.


Individuals with an inherited deficiency in gonadotropin-releasing hormone (GnRH) have impaired sexual reproduction. Previous genetic linkage studies and sequencing of plausible gene candidates have identified mutations associated with inherited GnRH deficiency, but the small number of affected families and limited success in validating candidates have impeded genetic diagnoses for most patients. Using a combination of exome sequencing and computational modeling, we have identified a shared point mutation in semaphorin 3E (SEMA3E) in 2 brothers with Kallmann syndrome (KS), which causes inherited GnRH deficiency. Recombinant wild-type SEMA3E protected maturing GnRH neurons from cell death by triggering a plexin D1-dependent (PLXND1-dependent) activation of PI3K-mediated survival signaling. In contrast, recombinant SEMA3E carrying the KS-associated mutation did not protect GnRH neurons from death. In murine models, lack of either SEMA3E or PLXND1 increased apoptosis of GnRH neurons in the developing brain, reducing innervation of the adult median eminence by GnRH-positive neurites. GnRH neuron deficiency in male mice was accompanied by impaired testes growth, a characteristic feature of KS. Together, these results identify SEMA3E as an essential gene for GnRH neuron development, uncover a neurotrophic function for SEMA3E in the developing brain, and elucidate SEMA3E/PLXND1/PI3K signaling as a mechanism that prevents GnRH neuron deficiency.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Animals
  • Cell Adhesion Molecules, Neuronal / genetics
  • Cell Adhesion Molecules, Neuronal / metabolism
  • Cytoskeletal Proteins
  • Exome
  • Glycoproteins / genetics
  • Glycoproteins / metabolism*
  • Gonadotropin-Releasing Hormone / deficiency*
  • Humans
  • Kallmann Syndrome / genetics
  • Kallmann Syndrome / metabolism*
  • Kallmann Syndrome / pathology
  • Male
  • Membrane Glycoproteins / genetics
  • Membrane Glycoproteins / metabolism
  • Membrane Proteins / genetics
  • Membrane Proteins / metabolism*
  • Mice
  • Mice, Mutant Strains
  • Mutation*
  • Nerve Tissue Proteins / genetics
  • Nerve Tissue Proteins / metabolism
  • Neurons / metabolism*
  • Neurons / pathology
  • Phosphatidylinositol 3-Kinases / genetics
  • Phosphatidylinositol 3-Kinases / metabolism
  • Semaphorins / genetics
  • Semaphorins / metabolism*
  • Signal Transduction / genetics


  • Cell Adhesion Molecules, Neuronal
  • Cytoskeletal Proteins
  • Glycoproteins
  • Membrane Glycoproteins
  • Membrane Proteins
  • Nerve Tissue Proteins
  • PLXND1 protein, human
  • Plxnd1 protein, mouse
  • SEMA3E protein, human
  • Sema3e protein, mouse
  • Semaphorins
  • Gonadotropin-Releasing Hormone