CCDC141 Mutation Identified in Anosmic Hypogonadotropic Hypogonadism (Kallmann Syndrome) Alters GnRH Neuronal Migration.

The first mutation in a gene associated with a neuronal migration disorder was identified in patients with Kallmann Syndrome, characterized by hypogonadotropic hypogonadism and anosmia. This pathophysiological association results from a defect in the development of the GnRH and the olfactory system. A recent genetic screening of Kallmann Syndrome patients revealed a novel mutation in CCDC141. Little is known about CCDC141, which encodes a coiled-coil domain containing protein. Here, we show that Ccdc141 is expressed in GnRH neurons and olfactory fibers and that knockdown of Ccdc141 reduces GnRH neuronal migration. Our findings in human patients and mouse models predict that CCDC141 takes part in embryonic migration of GnRH neurons enabling them to form a hypothalamic neuronal network to initiate pulsatile GnRH secretion and reproductive function.

A liver specific gene that is expressed in growth hormone transgenic mice and in normal female mice as a function of age.

Growth hormone (GH) acts on various organs to exert its growth and metabolic effects. GH induces transcription of a number of genes in different organs including liver. By performing subtractive hybridization analysis on liver cDNAs of GH transgenic and non-transgenic mice, differentially expressed cDNAs were obtained. This paper describes the isolation and characterization of a liver cDNA, termed cDNA #5, that contains 1897 bp and is predicted to encode a protein (P5) of 512 aa residues. P5 has five immunoglobulin related domains thus allowing it to be classified as a member of the immunoglobulin super family (IGSF). Also, P5 shows significant similarity to both rat and human alpha-1-B glycoprotein which is an acidic serum protein of unknown function. mRNA #5 was detected in the liver hepatocytes of male and female GH transgenic mice and in the liver of female, but not of male, non-transgenic mice. mRNA #5 was not present in dwarf mice including the Ames dwarf, those that express a GH antagonist and those with the GH receptor and binding protein gene disrupted. These findings suggest that induction of mRNA #5 in the liver requires a continuous pattern of GH secretion and an intact GH-GH receptor-signaling complex. mRNA #5 levels in female non-transgenic mice were observed to vary with age implying that gender-specific age-dependent factor(s) may be involved in the induction of mRNA #5. The appearance of mRNA #5 in post-hepatectomized liver that coincides with the proliferative phase of liver regeneration suggests that it may be involved in hepatocyte proliferation. Together these data suggest that expression of cDNA #5 is liver-specific, sexually dimorphic, age-dependent, and may be involved in hepatocyte hyperplasia and liver enlargement.

Gonadotropin releasing hormone-1 expression in incisors of mice.

GnRH-1 is a decapeptide hormone that regulates gonadal maturation and fertility. In brain, GnRH-1 is secreted by neurons residing mainly in the preoptic/hypothalamic area. These neurons arise from cells in the nasal placode during embryonic development. GnRH-1 mRNA and peptide in the nonhypothalamic region have been described, suggesting other functions of GnRH-1. This paper describes for the first time the expression of GnRH-1 in developing incisors in mice. At embryonic day (E) 12.5, GnRH-1 mRNA and peptide were localized in cells in oral and dental epithelia. At postnatal day (P) 6, before incisor eruption, GnRH-1 was expressed in cells in dental epithelial-derived structures that include the papillary layer, outer dental epithelium, stellate reticulum, stratum intermedium, and enamel-secreting ameloblast cell layer. GnRH-1 expression correlated with cell maturity, becoming stronger in cells farther away from the proliferative zone. From E12.5 through P6, GnRH-1 expression was not detected in neural crest-derived dental mesenchyme or in mesenchyme-derived structures that include dental papilla, dental follicle, and dentin-secreting odontoblast. In addition, GnRH-1 expression was not detected in molars, indicating that expression of GnRH-1 is differentially regulated in incisor vs. molars, with only the former exhibiting continuous growth in this species. In homozygous hypogonadal mice at P1, GnRH-1 peptide expression was not detected, yet incisors were present. However, morphological changes in cells between dental follicle and ameloblast cell layer were noted. Taken together, our results indicate that GnRH-1 expression, although not essential for initiation and formation of incisors, may be important in maturation and/or maintenance of these placodally derived structures.