Dysregulation of Semaphorin7A/β1-integrin signaling leads to defective GnRH-1 cell migration, abnormal gonadal development and altered fertility

Hum Mol Genet. 2011 Dec 15;20(24):4759-74. doi: 10.1093/hmg/ddr403. Epub 2011 Sep 8.


Reproduction in mammals is dependent on the function of specific neurons that secrete gonadotropin-releasing hormone-1 (GnRH-1). These neurons originate prenatally in the nasal placode and migrate into the forebrain along the olfactory-vomeronasal nerves. Alterations in this migratory process lead to defective GnRH-1 secretion, resulting in heterogeneous genetic disorders such as idiopathic hypogonadotropic hypogonadism (IHH), and other reproductive diseases characterized by the reduction or failure of sexual competence. Combining mouse genetics with in vitro models, we demonstrate that Semaphorin 7A (Sema7A) is essential for the development of the GnRH-1 neuronal system. Loss of Sema7A signaling alters the migration of GnRH-1 neurons, resulting in significantly reduced numbers of these neurons in the adult brain as well as in reduced gonadal size and subfertility. We also show that GnRH-1 cells differentially express the Sema7 receptors β1-integrin and Plexin C1 as a function of their migratory stage, whereas the ligand is robustly expressed along developing olfactory/vomeronasal fibers. Disruption of Sema7A function in vitro inhibits β1-integrin-mediated migration. Analysis of Plexin C1(-/-) mice did not reveal any difference in the migratory process of GnRH-1 neurons, indicating that Sema7A mainly signals through β1-integrin to regulate GnRH-1 cell motility. In conclusion, we have identified Sema7A as a gene implicated in the normal development of the GnRH-1 system in mice and as a genetic marker for the elucidation of some forms of GnRH-1 deficiency in humans.

Publication types

  • Research Support, N.I.H., Intramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antigens, CD / metabolism*
  • Axons / metabolism
  • Brain / embryology
  • Brain / pathology
  • Cell Count
  • Cell Movement*
  • Fertility*
  • Gonadotropin-Releasing Hormone / metabolism*
  • Gonads / abnormalities
  • Gonads / embryology*
  • Gonads / metabolism
  • Gonads / pathology
  • Humans
  • Integrin beta1 / metabolism*
  • Male
  • Mice
  • Nerve Tissue Proteins / metabolism
  • Neurons / metabolism
  • Neurons / pathology
  • Olfactory Bulb / embryology
  • Olfactory Bulb / metabolism
  • Protein Precursors / metabolism*
  • Receptors, Cell Surface / metabolism
  • Semaphorins / deficiency
  • Semaphorins / metabolism*
  • Signal Transduction*
  • Testis / embryology
  • Testis / metabolism
  • Testis / pathology
  • Vomeronasal Organ / embryology
  • Vomeronasal Organ / metabolism


  • Antigens, CD
  • Integrin beta1
  • Nerve Tissue Proteins
  • Plxna3 protein, mouse
  • Protein Precursors
  • Receptors, Cell Surface
  • Sema7a protein, mouse
  • Semaphorins
  • progonadoliberin I
  • Gonadotropin-Releasing Hormone