Suppression of ß1-integrin in gonadotropin-releasing hormone cells disrupts migration and axonal extension resulting in severe reproductive alterations.

ABSTRACT

Reproduction in mammals is dependent on the function of hypothalamic neurons whose axons project to the hypothalamic median eminence (ME) where they release gonadotropin-releasing hormone (GnRH) into a specialized capillary network for delivery to the anterior pituitary. These neurons originate prenatally in the nasal placode and migrate into the forebrain along the olfactory-vomeronasal nerves. The complex developmental events leading to the correct establishment of the GnRH system are tightly regulated by the specific spatiotemporal expression patterns of guidance cues and extracellular matrix molecules, the functions of which, in part, are mediated by their binding to ß1-subunit-containing integrins. To determine the biological role of these cell-surface proteins in reproduction, Cre/LoxP technology was used to generate GnRH neuron-specific ß1-integrin conditional KO (GnRH-Itgb1(-/-)) mice. Loss of ß1-integrin signaling impaired migration of GnRH neurons, their axonal extension to the ME, timing of pubertal onset, and fertility in these mice. These results identify ß1-integrin as a gene involved in normal development of the GnRH system and demonstrate a fundamental role for this protein in acquisition of normal reproductive competence in female mice.