Migratory arrest of gonadotropin-releasing hormone neurons in transgenic mice.

Abstract

Gonadotropin-releasing hormone (GnRH) is important in reproduction, although the mechanism of central hypogonadism in humans remains unclear. Because the GnRH neuron originates from the olfactory placode and migrates to the hypothalamus during development, central hypogonadism in humans could be caused by failure in normal migration of GnRH neurons to the hypothalamus. We report that in transgenic mice expression of the simian virus 40 T antigen, driven by the promoter of human GnRH gene, resulted in central hypogonadism due to an arrest in neuronal migration during development and tumor formation along the migratory pathway. This system appears to be an important animal model of hypogonadotropic hypogonadism in humans. Additionally, olfactory bulb tumors from these animals were dispersed, and a GnRH-secreting neuronal cell line (GN cell line) was established.

Diversity of actions of GnRHs mediated by ligand-induced selective signaling

“…Some detailed mapping and functional analyses of GnRH I and GnRH II neurons have been performed in mammals [28,29,131,145]. However, the action of GnRH on GnRH neurons or their neighboring cells has not been characterized in great depth, although several model cell lines, derived from mouse hypothalamic GnRH neurons, have provided the foundations for further functional studies [84,119]. More recently, the role of the metastin/kisspeptin receptor (gpr54) in influencing GnRH neuron function has been elucidated [30,85,117,138], but how mammalian GnRH I and GnRH II and the type I or type II GnRH receptors integrate into the complexity of neuronal function, in both males and females, still requires further elaboration.…”

Expression and Function of Gonadotropin-releasing Hormone (GnRH) Receptor in Human Olfactory GnRH-secreting Neurons

“…Two immortalized GnRH-expressing neuronal cell lines, GT1 and GN, represent useful model systems for in vitro study of GnRH neuron biology. These cell lines have been isolated from tumors induced by genetically targeting the expression of the simian virus 40 large T antigen in mouse GnRH neurons (5,6). Biochemical and functional studies have shown that these cells retain many characteristics of hypothalamic GnRH-secreting neurons (7)(8)(9)(10).…”

“…Biochemical and functional studies have shown that these cells retain many characteristics of hypothalamic GnRH-secreting neurons (7)(8)(9)(10). GT1 cells derived from postmigratory hypothalamic tumor (5), whereas GN neuronal cells have been isolated from olfactory bulb tumor of migration-arrested GnRH neurons (6). The different origin may be indicative of some different maturational stages of the two cell lines, as demonstrated by the fact that GT1 cells retain many characteristics of the mature hypothalamic GnRH neurons (7)(8)(9)(10).…”

Adhesion-related Kinase Repression of Gonadotropin-releasing Hormone Gene Expression Requires Rac Activation of the Extracellular Signal-regulated Kinase Pathway

“…Two types of GnRH neuronal cell line exist, migratory and postmigratory. The GT-1 cells (and subclones GT1-1, GT1-3, and GT1-7) were isolated from an SV40 T antigen-targeted hypothalamic tumor of postmigratory GnRH neurons, whereas the GN10, GN11, and NLT GnRH neuronal cells were derived from an olfactory tumor of migratory arrested GnRH neurons (11,12). Like that observed in vivo, the GT cells express large amounts of GnRH and are nonmotile, whereas the GN/NLT cells express little GnRH and are intrinsically motile (6,7).…”