NELF knockout is associated with impaired pubertal development and subfertility.
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.
Section of Reproductive Endocrinology, Infertility, & Genetics, Department of Obstetrics & Gynecology; Department of Physiology; Georgia Regents University, Augusta, GA 30912, USA.
Samuel D
SD
Quaynor
Section of Reproductive Endocrinology, Infertility, & Genetics, Department of Obstetrics & Gynecology; Department of Physiology; Georgia Regents University, Augusta, GA 30912, USA.
Eun Kyung
EK
Ko
Section of Reproductive Endocrinology, Infertility, & Genetics, Department of Obstetrics & Gynecology; Department of Physiology; Georgia Regents University, Augusta, GA 30912, USA.
Lynn P
LP
Chorich
Section of Reproductive Endocrinology, Infertility, & Genetics, Department of Obstetrics & Gynecology; Department of Physiology; Georgia Regents University, Augusta, GA 30912, USA.
Megan E
ME
Sullivan
Department of Medical Biology and Genetics, Akdeniz University, Antalya 07058, Turkey.
Durkadin
D
Demir
Department of Biostatistics & Epidemiology, Georgia Regents University, Augusta, GA 30912, USA.
Jennifer L
JL
Waller
Section of Reproductive Endocrinology, Infertility, & Genetics, Department of Obstetrics & Gynecology; Department of Physiology; Georgia Regents University, Augusta, GA 30912, USA; Department of Neuroscience and Regenerative Medicine, Georgia Regents University, Augusta, GA 30912, USA.
Hyung-Goo
HG
Kim
Department of Medicine, Georgia Regents University, Augusta, GA 30912, USA; Department of Neuroscience and Regenerative Medicine, Georgia Regents University, Augusta, GA 30912, USA.
Richard S
RS
Cameron
Section of Reproductive Endocrinology, Infertility, & Genetics, Department of Obstetrics & Gynecology; Department of Physiology; Georgia Regents University, Augusta, GA 30912, USA; Department of Neuroscience and Regenerative Medicine, Georgia Regents University, Augusta, GA 30912, USA; Department of Physiology, Georgia Regents University, Augusta, GA 30912, USA. Electronic address: lalayman@gru.edu.
Lawrence C
LC
Layman
D000818:Animals; D002452:Cell Count; D002465:Cell Movement; D004971:Estrus / Q000235:genetics; D005260:Female; D005786:Gene Expression Regulation; D007987:Gonadotropin-Releasing Hormone / Q000096:biosynthesis / Q000235:genetics; D006720:Homozygote; D006801:Humans; D007030:Hypothalamo-Hypophyseal System / Q000002:abnormalities / Q000254:growth & development / Q000378:metabolism*; D007246:Infertility / Q000235:genetics* / Q000503:physiopathology; D008098:Litter Size; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D009474:Neurons / Q000378:metabolism* / Q000473:pathology; D012098:Reproduction / Q000235:genetics*; D012741:Sexual Maturation / Q000235:genetics; D015398:Signal Transduction; D014157:Transcription Factors / Q000172:deficiency* / Q000235:genetics; D014599:Uterus / Q000002:abnormalities / Q000254:growth & development / Q000378:metabolism*
C582413:NELF protein, mouse; D014157:Transcription Factors; D007987:Gonadotropin-Releasing Hormone
GnRH neuron migration; NELF; NSMF; infertility; nasal embryonic LHRH factor