Open AccessExploring the Potential Role of DLK1 in Pubertal Initiation
Author(s) -
Youn Hee Jee,
Angela Delaney,
Melissa Jennings,
Jack A. Yanovski,
Jeffrey Baron
Publication year - 2021
Publication title -
journal of the endocrine society
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.046
H-Index - 20
ISSN - 2472-1972
DOI - 10.1210/jendso/bvab048.1361
Subject(s) - medicine , endocrinology , receptor , hypothalamus , precocious puberty , biology , chemistry , hormone
The mechanisms that orchestrate the initiation of puberty are not well understood. DLK1 encodes a transmembrane protein that interacts with NOTCH1 receptor to negatively regulate NOTCH signaling. Loss-of-function mutations in DLK1 cause central precocious puberty, suggesting that DLK1 normally inhibits the reproductive axis centrally. The soluble form of DLK1, which is generated by proteolytic cleavage of the DLK1 extracellular domain, is measurable in human serum. We hypothesized that serum soluble DLK1 concentrations decline with age and that the decline, either in circulating levels or in tissue expression, contributes to the physiological mechanisms triggering pubertal initiation. Serum DLK1 was measured by immunoassay in 102 healthy subjects (age newborn - 26 yrs, 54 male). DLK1 concentrations did not differ by sex, BMI SDS, height, or status of fasting. DLK1 concentrations declined overall with age (R2=0.04, P<0.001). However, there was not a substantial decline in the peripubertal period (mean± SEM, at Tanner stage 1, 2, 3, 4, 5: 14.8 ± 1.9, 16.4 ± 1.2, 17.0 ± 5, 13.6 ± 3, 9.7 ± 0.9 ng/mL). Serum DLK1, measured in 12 subjects (2 male) with a previous history of idiopathic central precocious puberty, did not differ from healthy controls. We next hypothesized that declining expression of Dlk1 or increasing expression of competing canonical NOTCH ligands in hypothalamus contributes to pubertal onset. The preoptic area (POA) was microdissected from rat brains (age 4 d, 2 w, 6 w, and 8-16 w, n=5 each) and expression was measured by RT-PCR. Dlk1 expression increased with age in both female and male rats (P<0.001). Notch1 expression did not change with age. Expression of two ligands, Jag1 and Dll4, showed a peak at age 6 w, around the time of puberty, but only in males, and none of the other ligands (Jag1, Dll1, and Dll3) showed increasing expression at the age of puberty. In conclusion, we did not find evidence that declining serum soluble DLK1 concentrations in humans, declining DLK1 expression in rat preoptic area, or increasing NOTCH ligand expression in rat preoptic area contribute to pubertal onset.