Expression of a Tumor-Related Gene Network Increases in the Mammalian Hypothalamus at the Time of Female Puberty

Abstract

Much has been learned in recent years about the central mechanisms controlling the initiation of mammalian puberty. It is now clear that this process requires the interactive participation of several genes. Using a combination of high throughput, molecular, and bioinformatics strategies, in combination with a system biology approach, we singled out from the hypothalamus of nonhuman primates and rats a group of related genes whose expression increases at the time of female puberty. Although these genes [henceforth termed tumorrelated genes ( D URING THE LAST few years, significant progress has been made toward elucidating the basic cellular and molecular mechanisms underlying the neuroendocrine control of mammalian puberty. Specific transsynaptic and gliato-neuron communication pathways affecting the GnRH neuronal network have been identified, and the relative importance of each of these pathways in controlling the pubertal process has been demonstrated, along with some of their structural and functional interactions. The neuronal networks most critically involved in controlling GnRH release during sexual development have been shown to be those that use excitatory/inhibitory amino acids (reviewed in Ref. 1), and the recently identified neuropeptide metastin/ kisspeptin (2, 3), for neurotransmission. Cell-cell signaling molecules that, produced in astroglial cells, facilitate GnRH secretion have been identified, and genetic approaches have been used to define the physiological contribution of these molecules to the pubertal process (reviewed in Ref. 4).These efforts have also made clear that no isolated pathway or cellular subset is responsible for the neuroendocrine control of puberty. Instead, this control is likely exerted by complex regulatory gene networks composed of functional modules. A global approach for the system-level identification of such networks has never been attempted, essentially due to the lack of appropriate technology and the relative paucity of genetic and biochemical details that can be assimilated into a testable biological model. The emergence of high-throughput approaches and computational methods to organize, display, and analyze the plethora of results derived from such approaches is rapidly changing this landscape and giving us for the first time the opportunity of identifying functional genetic modules involved in the hierarchical control of puberty.Although mathematical models for common mechanisms of gene regulation are available (see, for instance, Ref. 5), most current models of genetic network architecture derive from nonmammalian species in which single metabolic or developmental pathways have been analyzed (e.g. Refs. 6 -8). The development of similar models to explain integrated functions of much more complex tissues, such as the hypothalamus, has been (and continues to be) exceedingly difficult because of the cellular heterogeneity of the nervous tissue, the lack of adequate sets of biochemical and genetic markers that can be used to build the network, the complexity of the...

Association weight matrix for the genetic dissection of puberty in beef cattle

“…Indeed, puberty is likely to be affected by many interacting genes that function in a network with a high degree of redundancy to preserve the essential process of reproduction. Our approach has predicted a large and redundant gene network for puberty, in agreement with previous results (17) and consistent with the endogenous topology of a network for an essential process (18).…”

“…However, the predicted interactions between RUNDC1 and BRCA1, as well as between RUNDC1 and NBR1, are yet to be tested. RUNDC1 is an inhibitor of the tumor suppressor p53 (23), a gene that embodies the link between oncogenes and reproduction (17,24). Evidence for coexpression of p53 and BRCA1 has been only very recently published (25).…”

Differential activation of kiss receptors by Kiss1 and Kiss2 peptides in the sea bass

“…Nevertheless, sea bass Kiss receptors possess conserved structural elements of the rhodopsin-like GPCR family, which have been shown to be necessary for correct receptor folding, activation, signaling and internalization of GPCRs (Lee et al 1999, Gloriam et al 2005, Oh et al 2006, Millar & Newton 2010. The additional characterization of the kissr promoter sequences of sea bass revealed that they contain putative conserved transcription factor binding sites similar to those observed in other teleosts (Mechaly et al 2010, Nocillado et al 2013 and mammals (Roth et al 2007). Of note, bioinformatic analysis of sea bass genes pointed to the presence of glucocorticoid receptor (GR) and progesterone receptor (PR) elements, suggesting that the kiss receptors genes are regulated by steroids, as described in the yellowtail kingfish and zebrafish (Nocillado et al (2013) and this study).…”

“…Of note, bioinformatic analysis of sea bass genes pointed to the presence of glucocorticoid receptor (GR) and progesterone receptor (PR) elements, suggesting that the kiss receptors genes are regulated by steroids, as described in the yellowtail kingfish and zebrafish (Nocillado et al (2013) and this study). Sea bass Kiss receptors may also be regulated by tumor-related genes such as transcription factor Wilms tumor 1 (WT1) and transcription factor Yin Yang 1 (YY1) (Roth et al 2007, Nocillado et al 2013), and it is also possible that photoperiod acts on the kissr genes at the level of expression as they contain C/EBP elements. In zebrafish, these elements correspond to the light-responsive D-box regulatory motif (Weger et al 2011).…”

ENDOCRINOLOGY AND ADOLESCENCE: Deciphering puberty: novel partners, novel mechanisms

“…On the contrary, let7 miRNAs were initially cataloged as putative tumor suppressors (88). Intriguingly, tumor-suppressor genes have been involved in the transcriptional control of puberty, with a detectable increase in its expression at the time of puberty (89). Whether let7 miRNAs fit into this category remains to be elucidated.…”