NELF knockout is associated with impaired pubertal development and subfertility

Abstract

Puberty and reproduction require proper signaling of the hypothalamic-pituitary-gonadal axis controlled by gonadotropin-releasing hormone (GnRH) neurons, which arise in the olfactory placode region and migrate along olfactory axons to the hypothalamus. Factors adversely affecting GnRH neuron specification, migration, and function lead to delayed puberty and infertility. Nasal embryonic luteinizing hormone-releasing factor (NELF) is a predominantly nuclear protein. NELF mutations have been demonstrated in patients with hypogonadotropic hypogonadism, but biallelic mutations are rare and heterozygous NELF mutations typically co-exist with mutations in another gene. Our previous studies in immortalized GnRH neurons supported a role for NELF in GnRH neuron migration. To better understand the physiology of NELF, a homozygous Nelf knockout (KO) mouse model was generated. Our findings indicate that female Nelf KO mice have delayed vaginal opening but no delay in time to first estrus, decreased uterine weight, and reduced GnRH neuron number. In contrast, male mice were normal at puberty. Both sexes of mice had impaired fertility manifested as reduced mean litter size. These data support that NELF has important reproductive functions. The milder than expected phenotype of KO mice also recapitulates the human phenotype since heterozygous NELF mutations usually require an additional mutation in a second gene to result in hypogonadotropic hypogonadism.

A Jacob/Nsmf Gene Knockout Results in Hippocampal Dysplasia and Impaired BDNF Signaling in Dendritogenesis

“…Sexual development, fertility hallmarks and reproductive capacity appear to be to a large extent normal. The results of the present work are in contrast to a recent report that claims subfertility and impaired puberty in female ko mice [ 22 ]. Our detailed analysis of a broad number of reproductive parameters clearly excludes subfertility and hypogonadotropic hypogonadism in both males and females.…”

KLB , encoding β‐Klotho, is mutated in patients with congenital hypogonadotropic hypogonadism

“…The reproductive defects in the KlbKO mice are less severe than the phenotypes observed in our CHH patients with heterozygous KLB mutations. This phenotypic discrepancy between human and mice has been previously reported for other CHH genes like TACR3 and NSMF (Yang et al, 2012;Quaynor et al, 2015). Notably, a similar reproductive phenotype was observed in KlbHET mice, indicating that Klb haploinsufficiency causes reproductive defects.…”

Anogenital distance and reproductive outcomes in 9‐ to 11‐year‐old boys: the INMA‐Granada cohort study

“…There is a lack of longitudinal data on AGD measurements from infancy to adulthood, but it is presumed that AGD markedly increases during puberty in association with development of the external genitalia and changes in body composition (Thankamony et al ., ). In rodents, AGD is used to determine pubertal onset because it depends on activation of the hypothalamic–pituitary–gonadal (HPG) axis by gonadal testosterone (Divall et al ., ; Quaynor et al ., ). However, there has been no research on the association of AGD with the sexual development of children.…”