Hypothalamic expression of DLK1 and MeCP2 in mice across pubertal development

• Grant number: 22/04870-9
• Support Opportunities: Scholarships abroad - Research Internship - Doctorate (Direct)
• Start date: July 26, 2022
• End date: February 25, 2023
• Field of knowledge: Health Sciences - Medicine - Medical Clinics
• Principal Investigator: Ana Claudia Latronico Xavier
• Grantee: Flávia Rezende Tinano
• Supervisor: Ursula Kaiser
• Host Institution: Faculdade de Medicina (FM). Universidade de São Paulo (USP). São Paulo , SP, Brazil
• Institution abroad: Brigham and Women's Hospital (BWH), United States
• Associated to the scholarship: 21/12205-2 - Investigation of genetic basis of Familial Central Precocious Puberty of maternal inheritance, BP.DD

Abstract

Central precocious puberty (CPP) is caused by premature re-emergence of pulsatile hypothalamic gonadotropin-releasing hormone (GnRH) secretion. The recognition of the genetic influence in this disturb has significantly increased after the description of loss-of-function mutations in two maternally imprinted genes (MKRN3 and DLK1) causing paternally transmitted CPP. The mechanisms of reactivation of the hypothalamic-pituitary-gonadal axis leading to the onset of puberty are not fully understood. Two different hypothalamic nuclei, the arcuate nucleus (ARC) and anteroventral periventricular nucleus (AVPV), are of particular interest regarding reproductive function due to the presence of kisspeptin neurons. After the identification of MKRN3 loss-of-function mutations in families with CPP, the measure of Mkrn3 mRNA levels in the ARC and AVPV of rodents and nonhuman primates was crucial to understanding the mechanism by which this gene represses the GnRH secretion. On the other hand, it´s still not determined how DLK1 interferes with pubertal onset, although its expression on mice´s hypothalamus was already proved. Aiming to identify new genes related to other forms of familial or sporadic CPP, we performed massive parallel sequencing in 86 probands with sporadic or familial CPP and identified potentially pathogenic variants in a X-linked gene (MECP2) in 3 patients with sporadic CPP, corroborated by the identification of another variant in the same gene in two British monogenic twin sisters. The relation of this new candidate gene with CPP is not yet elucidated. Although Mecp2 expression has been demonstrated in the hypothalamus of rats, the pattern of its expression across pubertal development has yet to be determined. Therefore, our objective is to characterize the expression pattern of Dlk1 and Mecp2 in mice hypothalamus across pubertal development, especially in the ARC and AVPV, as well as to investigate its co-expression in kisspeptin and GnRH neurons. (AU)

Scientific publications

(References retrieved automatically from Web of Science and SciELO through information on FAPESP grants and their corresponding numbers as mentioned in the publications by the authors)

MONTENEGRO, LUCIANA; SERAPHIM, CARLOS; TINANO, FLAVIA; PIOVESAN, MAIARA; CANTON, ANA P. M.; MCELREAVEY, KEN; BRABANT, SEVERINE; BORIS, NATALIA P.; MAGNUSON, MELISSA; CARROLL, RONA S.; et al. Familial central precocious puberty due to DLK1 deficiency: novel genetic findings and relevance of serum DLK1 levels. EUROPEAN JOURNAL OF ENDOCRINOLOGY, v. 189, n. 3, p. 7-pg., 2023-09-01. (22/04870-9, 21/12205-2, 19/27631-7, 22/00719-4)