Luteinizing Hormone/Chorionic Gonadotropin Receptor in Neuronal Development and Human Endocrine Diseases
Luteinizing hormone/choriogonadotropin receptor (LH/CG-R) plays a central role in human male sexual development. Mutation of the LH/CG-R results in abnormal production of testosterone and diseases of sexual development. Though the role of LH/CG-R in transducing the signal of luteinizing hormone/chorionic gonadotropin binding is well established, the mechanism of its action is still not fully understood. We had studied the molecular genetics of the LH/CG-R in a large number of patients with activating and inactivating mutations of the receptor. Studies of these naturally occurring mutations continue to help us understand the varied disease phenotype, as well as the molecular mechanism of receptor signal transduction.
Individuals with LH/CG-R carrying activating mutations develop familial male-limited precocious puberty and often have behavioral problems. The behavioral problem seen in patients with FMPP patients may be related to dysfunction of brain cells caused by the mutated receptor. Recent studies demonstrated human chorionic gonadotropin (hCG) and its receptor (LH/CG-R) may have nongonadal functions which could be important physiologically. In the nervous system LH/CG-R is expressed in the mammalian brain in a temporal and spatial pattern. Administration of hCG promoted nerve regeneration in vivo and neurite outgrowth and survival of primary neurons in vitro. To date the function of hCG and its receptor in the nervous system remains unclear.
To understand the role of hCG and its receptor in the development of the mammalian nervous system, we studied the effect of the transgenes on the differentiation of the bipotent cell line, PC12, derived from rat adrenal pheochromocytoma. Our studies showed that the differentiation effect of hCG was ligand dose- and time-dependent. Both the extracellular signal-regulated kinases (ERKs) and p38 mitogen-activated protein kinase (MAPK) were indispensable for the differentiation process. In addition, the Phospholipase C (PLC) pathway was partially involved in hCG induced PC12 differentiation. These findings imply a potential role of hCG/LH and LH/CG-R in the neurogenesis of the mammalian nervous system. Our studies also suggested that hCG promotes myelination through inducing myelin protein zero (P0) expression. the findings of these studies suggest that hCG/LH and its receptor participate in the development and maintenance of the mammalian nervous system. hCG may be a potential regeneration drug for future treatment of acute neural injuries or neurodegenerative disorders.
Discovery of the presence of LH/CG-R with germline and somatic activating mutations in patients with testicular tumor raised the question of its (mutated LH/CG-R) potential tumorigenic effect . Two patients with the activating mutation Asp578Gly mutation developed Leydig cell neoplasia, while a somatic Asp578His activating mutation was identified in a number of testicular tumor patients. Animal studies have so far failed to establish lines of male or female transgenic founder mice carrying LH/CG-R with the Asp578His mutation indicative of inherent differences between the germline and the somatic mutations. To explore the difference in the biological effects between the two mutations, a MA-10 Leydig cell model was established by stable transfection with the two mutant human receptors, LH/CG-R-Asp578Gly and LH/CG-R-Asp578His. Examination of gene expression profiles using cDNA microarray and a systems biological approach, hierarchical clustering and multi-dimensional scaling analysis , the wild type and the two mutants could be distinguished . The expression of 54 genes was altered by the presence of LH/CG-R Asp578Gly mutation, while 49 genes were changed in the presence of the LH/CG-R Asp578His mutation. By comparing both mutants to the wild type, 132 genes were found to be differentially expressed. Novel regulatory pathways unique to each mutation were identified; 9 networks in LH/CG-R-Asp578Gly expressing cells, and 12 in LH/CG-R-Asp578His expressing cells. Further analyses showed c-Myc and c-Src to be the key regulators associated with Asp578Gly and Asp578His mutants, respectively. The involvement of these two factors was confirmed by molecular and functional assays. The results open a new dimension and provide a novel explanation for the role of LH/CG-R mutation in testicular tumorigenesis.