In mammals, including humans, puberty onset reflects the activation of the neuroendocrine reproductive axis, and adolescence is therefore a time of key physiological, anatomical, behavioral, and psychological changes. However, the specific processes timing and governing the activation of the reproductive axis during pubertal maturation and earlier developmental stages remain poorly understood, as does the reason for earlier sexual maturation in girls than boys. Similarly, the reason for a higher incidence of precocious puberty in girls and delayed puberty in boys is unclear. Recently, the neuropeptide kisspeptin, and its receptor Kiss1R, have been implicated in pubertal development and adulthood fertility. Encoded by the Kiss1 gene, kisspeptin stimulates GnRH secretion in mammals, including humans, and mutations in Kiss1 or Kiss1R impair fertility and puberty in rodents and humans. Despite evidence linking hypothalamic Kiss1 neurons to the control of reproduction in adulthood, less attention has recently been given to the role of Kiss1 neurons prior to adulthood. The overall goal of this proposal is to investigate the role of the Kiss1 system in the sex-specific regulation the reproductive axis in postnatal and pubertal development.
Aim I will investigate the importance of kisspeptin signaling in the secretion of gonadal steroids during the postnatal "critical period", a process which directs sexual differentiation of the brain. Experiments in this aim will assess whether postnatal gonadal steroid secretion is impaired in mice lacking kisspeptin signaling, if kisspeptin treatment can induce gonadal steroid secretion in postnatal females, and whether Kiss1 neurons in specific brain nuclei are activated during postnatal gonadal steroid secretion.
Aim II will explore the role of the Kiss1 system in key stages of pubertal maturation. Experiments in this aim will determine when and where (in the brain) Kiss1 neurons first become activated during peripubertal development, whether changes in Kiss1R comprise a key element of pubertal development, and whether acute, short-term blockade of central or peripheral kisspeptin signaling impairs puberty onset.
Aim III will investigate the role of both gonadal hormones and non-gonadal factors in regulating Kiss1 neurons during peripubertal development. Experiments in this aim will analyze whether pubertal changes in hormone sensitivity of the reproductive axis reflect developmental changes in the sensitivity of Kiss1 neurons to hormone feedback, assess the timing of developmental changes in gonadal hormone-independent regulation of Kiss1 neurons in relation to puberty onset, and elucidate whether sex differences in peripubertal Kiss1 neurons are organized by hormones during early postnatal life. Overall, this proposal will provide a better understanding of how and when the reproductive axis is regulated during different critical stages of development, as well as where in the brain such regulation is specifically derived. This information could provide important insight into the mechanisms underlying hypogonadotropic hypogonadism, precious puberty, and delayed puberty.

Public Health Relevance

Adolescence is a time of critical physiological, behavioral, and psychological changes, but the precise molecular, cellular, and neural mechanisms underlying the regulation of pubertal development remain one of the enigmas of modern science. This proposal investigates the role of hormones and kisspeptin signaling in the regulation of the reproductive axis during key periods of development, including the postnatal "critical period" and sexual maturation (puberty). This work will contribute to our understanding of the critical role of hormones and neural circuits in essential reproductive and developmental processes, and will provide further insight into the mechanisms responsible for various human reproductive disorders and diseases, such as idiopathic hypogonadotropic hypogonadism, nutritional infertility, oligomenorrhea, polycystic ovarian syndrome, and precocious or delayed puberty.

Agency
National Institute of Health (NIH)
Institute
Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD)
Type
Research Project (R01)
Project #
5R01HD065856-03
Application #
8319426
Study Section
Integrative and Clinical Endocrinology and Reproduction Study Section (ICER)
Program Officer
Winer, Karen
Project Start
2010-08-10
Project End
2015-07-31
Budget Start
2012-08-01
Budget End
2013-07-31
Support Year
3
Fiscal Year
2012
Total Cost
$300,604
Indirect Cost
$101,404
Name
University of California San Diego
Department
Obstetrics & Gynecology
Type
Schools of Medicine
DUNS #
804355790
City
La Jolla
State
CA
Country
United States
Zip Code
92093
Semaan, Sheila J; Kauffman, Alexander S (2015) Daily successive changes in reproductive gene expression and neuronal activation in the brains of pubertal female mice. Mol Cell Endocrinol 401:84-97
Koemeter-Cox, Andrew I; Sherwood, Thomas W; Green, Jill A et al. (2014) Primary cilia enhance kisspeptin receptor signaling on gonadotropin-releasing hormone neurons. Proc Natl Acad Sci U S A 111:10335-40
Tolson, Kristen P; Garcia, Christian; Yen, Stephanie et al. (2014) Impaired kisspeptin signaling decreases metabolism and promotes glucose intolerance and obesity. J Clin Invest 124:3075-9
Poling, Matthew C; Shieh, Morris P; Munaganuru, Nagambika et al. (2014) Examination of the influence of leptin and acute metabolic challenge on RFRP-3 neurons of mice in development and adulthood. Neuroendocrinology 100:317-33
Hoffmann, Hanne M; Tamrazian, Anika; Xie, Huimin et al. (2014) Heterozygous deletion of ventral anterior homeobox (vax1) causes subfertility in mice. Endocrinology 155:4043-53
Di Giorgio, Noelia P; Catalano, Paolo N; Lopez, Paula V et al. (2013) Lack of functional GABAB receptors alters Kiss1 , Gnrh1 and Gad1 mRNA expression in the medial basal hypothalamus at postnatal day 4. Neuroendocrinology 98:212-23
Witham, Emily A; Meadows, Jason D; Hoffmann, Hanne M et al. (2013) Kisspeptin regulates gonadotropin genes via immediate early gene induction in pituitary gonadotropes. Mol Endocrinol 27:1283-94
Semaan, Sheila J; Kauffman, Alexander S (2013) Emerging concepts on the epigenetic and transcriptional regulation of the Kiss1 gene. Int J Dev Neurosci 31:452-62
Kim, Joshua; Tolson, Kristen P; Dhamija, Sangeeta et al. (2013) Developmental GnRH signaling is not required for sexual differentiation of kisspeptin neurons but is needed for maximal Kiss1 gene expression in adult females. Endocrinology 154:3273-83
Poling, M C; Quennell, J H; Anderson, G M et al. (2013) Kisspeptin neurones do not directly signal to RFRP-3 neurones but RFRP-3 may directly modulate a subset of hypothalamic kisspeptin cells in mice. J Neuroendocrinol 25:876-86

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