Sex-specific regulation of weight and puberty by the Lin28/let-7 axis

Abstract

Growth and pubertal timing differ in boys and girls. Variants in/nearLIN28Bassociate with age at menarche (AAM) in genome-wide association studies and some AAM-related variants associate with growth in a sex-specific manner. Sex-specific growth patterns in response toLin28bperturbation have been detected in mice, and overexpression ofLin28ahas been shown to alter pubertal timing in female mice. To investigate further howLin28aandLin28baffect growth and puberty in both males and females, we evaluatedLin28bloss-of-function (LOF) mice andLin28again-of-function (GOF) mice. Because bothLin28aandLin28bcan act via the conserved microRNAlet-7, we also examinedlet-7GOF mice. As reported previously,Lin28bLOF led to lighter body weights only in male mice whileLin28aGOF yielded heavier mice of both sexes.Let-7GOF mice weighed less than controls, and males were more affected than females. Timing of puberty was assessed by vaginal opening (VO) and preputial separation (PS). MaleLin28bLOF and malelet-7GOF, but not female, mice displayed alteration of pubertal timing, with later PS than controls. In contrast, both male and femaleLin28aGOF mice displayed late onset of puberty. Together, these data point toward a complex system of regulation byLin28a,Lin28b, andlet-7, in whichLin28bandlet-7can impact both puberty and growth in a sex-specific manner, raising the possibility that this pathway may contribute to differential regulation of male and female growth and puberty in humans.