Dysregulation of semaphorin7A/β1-integrin signaling leads to defective GnRH-1 cell migration, abnormal gonadal development and altered fertility

Andrea Messina, Nicoletta Ferraris, Susan Wray, Gabriella Cagnoni, Duncan E. Donohue, Filippo Casoni, Phillip R. Kramer, Alwin A. Derijck, Youri Adolfs, Aldo Fasolo, Ronald J. Pasterkamp, Paolo Giacobini

Research output: Contribution to journalArticlepeer-review

Abstract

Reproduction in mammals is dependent on the function of specific neurons that secrete gonadotropinreleasing 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.

Original languageEnglish
Article numberddr403
Pages (from-to)4759-4774
Number of pages16
JournalHuman Molecular Genetics
Volume20
Issue number24
DOIs
Publication statusPublished - Dec 2011

ASJC Scopus subject areas

  • Genetics
  • Genetics(clinical)
  • Molecular Biology

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