The hypothalamic-pituitary-gonadal (HPG) axis regulates puberty initiation and reproductive function. This axis is active during the embryonic and neonatal stages of human life but then suppressed during childhood, then ultimately re-activated, first detected as an increase in amplitude and frequency of gonadotropin-releasing hormone (GnRH) pulses, to initiate puberty. The re-emergence of pulsatile GnRH release leads to increases in the secretion of the pituitary gonadotropins, luteinizing hormone (LH) and follicle stimulating hormone (FSH), and consequent activation of gonadal function. Pubertal timing is influenced by complex interactions of genetic, nutritional, environmental and socioeconomic factors. Early activation of the HPG axis results in gonadotropin- dependent or central precocious puberty (CPP), clinically defined by the development of secondary sexual characteristics before age 8 years in girls and 9 years in boys. The timing of puberty is associated with risks of subsequent disease; earlier age of menarche in girls is associated with increased risks of breast cancer, endometrial cancer, obesity, type 2 diabetes and cardiovascular disease. The genetic determinants of the timing of human pubertal development and in particular CPP are largely unknown. We recently identified loss- of-function mutations in the imprinted MKRN3 gene, encoding makorin ring finger protein 3, in patients with CPP, using whole exome sequencing. Mkrn3is highly expressed in the arcuate nucleus of juvenile mice, with a marked reduction prior to puberty onset. Based on these data, we hypothesize that MKRN3 acts as a brake for GnRH release during the dormant prepubertal phase, the first peptide identified to have such an inhibitory role. However, little is known about the function of this protein. The long-term goal of this project is to elucidate the molecular, cellular, and physiologic mechanisms by which MKRN3 controls the timing of puberty onset, and by which MKRN3 mutations result in early activation of the central reproductive axis. In the first aim, we will identify novel MKRN3 defects in patients with CPP and expand our understanding of the phenotype of patients with MKRN3 deficiency. In the second aim, we will determine the reproductive role of Mkrn3 in vivothrough a series of expression and functional studies in mice with and without functional Mkrn3. In the third aim, we will identify MKRN3 partners and/or targets in vitro by performing capture proteomics in a neuronal cell line as well as comparing gene expression profiles in neuronal progenitor cells derived from human induced pluripotent stem cells with and without functional MKRN3. The successful completion of these aims will help us to understand the actions of MKRN3, a novel regulator of GnRH re-activation, in the neuroendocrine control of pubertal timing and may also have a broader role in neuronal differentiation, development and maturation. A complete understanding of the role of MRKN3 in GnRH regulation may also identify novel factors involved in the neuroendocrine control of reproduction, and lead to the development of new tools for the management of reproductive disorders.

Public Health Relevance

The time of puberty is influenced by complex interactions of genetic, nutritional, environmental and socioeconomic factors. However, the genetic determinants of the timing of puberty and in particular early or central precocious puberty are largely unknown. The objective of this proposal is to provide insights that will help us to understand the control of pubertal timing, identify novel factors involved in the neuroendocrine control of puberty, and lead to the development of new tools for the management of pubertal and reproductive disorders.

Agency
National Institute of Health (NIH)
Institute
Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD)
Type
Research Project (R01)
Project #
5R01HD082314-04
Application #
9415048
Study Section
Integrative and Clinical Endocrinology and Reproduction Study Section (ICER)
Program Officer
Winer, Karen
Project Start
2015-04-01
Project End
2020-01-31
Budget Start
2018-02-01
Budget End
2019-01-31
Support Year
4
Fiscal Year
2018
Total Cost
Indirect Cost
Name
Brigham and Women's Hospital
Department
Type
DUNS #
030811269
City
Boston
State
MA
Country
United States
Zip Code
Macedo, Delanie B; Fran├ža, Monica M; Montenegro, Luciana R et al. (2018) Central Precocious Puberty Caused by a Heterozygous Deletion in the MKRN3 Promoter Region. Neuroendocrinology 107:127-132
Rich-Edwards, Janet W; Kaiser, Ursula B; Chen, Grace L et al. (2018) Sex and Gender Differences Research Design for Basic, Clinical, and Population Studies: Essentials for Investigators. Endocr Rev 39:424-439
Ross, Rachel A; Leon, Silvia; Madara, Joseph C et al. (2018) PACAP neurons in the ventral premammillary nucleus regulate reproductive function in the female mouse. Elife 7:
Dauber, Andrew; Cunha-Silva, Marina; Macedo, Delanie B et al. (2017) Paternally Inherited DLK1 Deletion Associated With Familial Central Precocious Puberty. J Clin Endocrinol Metab 102:1557-1567
Zheng, Junjie; Mao, Jiangfeng; Xu, Hongli et al. (2017) Pulsatile GnRH Therapy May Restore Hypothalamus-Pituitary-Testis Axis Function in Patients With Congenital Combined Pituitary Hormone Deficiency: A Prospective, Self-Controlled Trial. J Clin Endocrinol Metab 102:2291-2300
Ercan, Altan; Kohrt, Wendy M; Cui, Jing et al. (2017) Estrogens regulate glycosylation of IgG in women and men. JCI Insight 2:e89703
Bessa, Danielle S; Macedo, Delanie B; Brito, Vinicius N et al. (2017) High Frequency of MKRN3 Mutations in Male Central Precocious Puberty Previously Classified as Idiopathic. Neuroendocrinology 105:17-25
Maguire, Caroline A; Song, Yong Bhum; Wu, Min et al. (2017) Tac1 Signaling Is Required for Sexual Maturation and Responsiveness of GnRH Neurons to Kisspeptin in the Male Mouse. Endocrinology 158:2319-2329
Lee, Hyunju; Hodi, F Stephen; Giobbie-Hurder, Anita et al. (2017) Characterization of Thyroid Disorders in Patients Receiving Immune Checkpoint Inhibition Therapy. Cancer Immunol Res 5:1133-1140
Abreu, Ana Paula; Kaiser, Ursula B (2016) Pubertal development and regulation. Lancet Diabetes Endocrinol 4:254-264

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