The Lin28/let-7 axis regulates pubertal timing in a sex-dependent manner in mice

Program: Abstracts - Orals, Featured Poster Presentations, and Posters
Session: SAT 596-621-Pediatric Endocrinology /Steroids and Puberty
Saturday, June 15, 2013: 1:45 PM-3:45 PM
Expo Halls ABC (Moscone Center)

Poster Board SAT-605
Christina Alm*1, Gen Shinoda2, Hao Zhu2, Diana Cousminer1, Christine Crossman1, George Q Daley2 and Mark R Palmert1
1The Hosp for Sick Children, Toronto, ON, Canada, 2Children's Hosp Boston, Boston, MA
Pubertal timing varies within the population and differs between girls and boys, with girls more likely to exhibit precocious puberty and boys more likely to experience delayed puberty. The factors that regulate the timing of puberty and contribute to these male-female differences are largely unknown. Recently, LIN28B has been associated with age at menarche in women in several GWA studies. Subsequently, female mice overexpressing Lin28a, a homologue of Lin28b, were shown to have later pubertal onset than control mice, providing further evidence that the Lin28a/Lin28b pathway regulates pubertal timing. Lin28a and Lin28b inhibit maturation of let-7 microRNAs, which control cellular differentiation and developmental processes.

To examine how the Lin28/let-7 axis affects puberty in males and females and to investigate whether this regulation is let-7-dependent, we determined the timing of puberty in Lin28b-deficient mice and in let-7 overexpressing mice. Pubertal timing was assessed using preputial separation (PS) in males and vaginal opening (VO) in females.

Because Lin28a gain-of-function female mice have later VO, we expected Lin28b-deficient and let-7 overexpressing mice to have earlier puberty. Surprisingly, pubertal timing was unaffected in both Lin28b-deficient and let-7 gain-of-function (GOF) female mice. In contrast, Lin28b-deficient male mice as well as let-7 GOF male mice reached PS two days later than wildtype littermate controls (28.8 +/- 2.4 vs 26.9 +/- 1.8 for Lin28b-/-  and 28.4 +/- 2.0 vs 26.1 +/- 1.4 for let-7 GOF, respectively; p<0.01 for both strains). The delayed puberty cannot be explained by delayed growth; the let-7 GOF male mice were larger than controls at puberty (p<0.05). The sex-specific phenotypes were observed despite evidence that Lin28b was knocked out and that increased levels of mature let-7miRNA were present in both sexes.

Combined, our data strongly suggest that the Lin28/let-7 pathway regulates puberty in a sex-specific manner. In addition, Lin28b may regulate puberty more robustly in males than in females, and regulation of female puberty may, in part, be let-7 independent. These findings provide new opportunities to investigate how male and female puberty is differentially regulated.

Nothing to Disclose: CA, GS, HZ, DC, CC, GQD, MRP

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