Suppression of β1-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 β1-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 β1-integrin conditional KO (GnRH-Itgb1−/−) mice. Loss of β1-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 β1-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.

Development of the neurons controlling fertility in humans: new insights from 3D imaging and transparent fetal brains

“…Indeed, using immunohistochemistry, many laboratories have assessed the number and distribution of GnRH neurons in the brains of several mammalian species, with estimates ranging from 800 cells in the entire brain in adult rodents to 2000 neurons in the hypothalamus of adult primates (Crowley et al, 2008;King and Anthony, 1984;Latimer et al, 2000;Silverman et al, 1982;Tobet et al, 2001). It is worth noting that the number of GnRH neurons in mice is higher during embryonic development (1000-1200 neurons) and declines at adulthood (Messina et al, 2011;Parkash et al, 2012). This might not be the case in humans, where GNRH1 mRNA-expressing cells remain widespread in hypothalamic as well as extrahypothalamic regions (Rance et al, 1994).…”

Shaping the Reproductive System: Role of Semaphorins in Gonadotropin-Releasing Hormone Development and Function

“…The relevance of Sema7A signaling in the correct development of the GnRH system has been confirmed by in vivo studies showing that both the loss of Sema7A expression and the conditional inactivation of β 1 -integrin in GnRH neurons impact the development of this system, resulting in the significant reduction of the GnRH neuronal population in the brain of adult mice, as well as reduced gonadal size and altered fertility [24,83]. …”

Mutation screening of SEMA3A and SEMA7A in patients with congenital hypogonadotropic hypogonadism

“…SEMA7A is able to promote axon outgrowth by signaling through integrin receptors containing the β1 subunit (13) and promotes directional migration of GnRH neurons through β1-integrin-dependent cell adhesion (10). β1-integrin signaling was also recently shown to be involved in the development of GnRH neuron axonal projections to the median eminence in mice (14). Sema7A −/− adult mice have a 30% reduction of GnRH-1 cells in their brains compared with wild-type mice, and innervation of the median eminence by GnRH-1 neuron fibers is also clearly reduced (10).…”