NELF knockout is associated with impaired pubertal development and subfertility

Samuel D. Quaynor, Eun Kyung Ko, Lynn P. Chorich, Megan E. Sullivan, Durkadin Demir, Jennifer L Waller, Hyung Goo Kim, Richard S Cameron, Lawrence C Layman

Research output: Contribution to journalArticle

11 Citations (Scopus)

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.

Original languageEnglish (US)
Pages (from-to)26-36
Number of pages11
JournalMolecular and Cellular Endocrinology
Volume407
DOIs
StatePublished - May 5 2015

Fingerprint

Luteinizing Hormone
Nose
Infertility
Gonadotropin-Releasing Hormone
Neurons
Mutation
Knockout Mice
Hypogonadism
Puberty
Genes
Delayed Puberty
Phenotype
Litter Size
Physiology
Estrus
Nuclear Proteins
Hypothalamus
Reproduction
Fertility
Axons

Keywords

  • GnRH neuron migration
  • Infertility
  • NELF
  • NSMF
  • Nasal embryonic LHRH factor

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Endocrinology

Cite this

NELF knockout is associated with impaired pubertal development and subfertility. / Quaynor, Samuel D.; Ko, Eun Kyung; Chorich, Lynn P.; Sullivan, Megan E.; Demir, Durkadin; Waller, Jennifer L; Kim, Hyung Goo; Cameron, Richard S; Layman, Lawrence C.

In: Molecular and Cellular Endocrinology, Vol. 407, 05.05.2015, p. 26-36.

Research output: Contribution to journalArticle

Quaynor, Samuel D. ; Ko, Eun Kyung ; Chorich, Lynn P. ; Sullivan, Megan E. ; Demir, Durkadin ; Waller, Jennifer L ; Kim, Hyung Goo ; Cameron, Richard S ; Layman, Lawrence C. / NELF knockout is associated with impaired pubertal development and subfertility. In: Molecular and Cellular Endocrinology. 2015 ; Vol. 407. pp. 26-36.
@article{2515a3a2d0184d649a19f1e97610aa00,
title = "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.",
keywords = "GnRH neuron migration, Infertility, NELF, NSMF, Nasal embryonic LHRH factor",
author = "Quaynor, {Samuel D.} and Ko, {Eun Kyung} and Chorich, {Lynn P.} and Sullivan, {Megan E.} and Durkadin Demir and Waller, {Jennifer L} and Kim, {Hyung Goo} and Cameron, {Richard S} and Layman, {Lawrence C}",
year = "2015",
month = "5",
day = "5",
doi = "10.1016/j.mce.2015.02.015",
language = "English (US)",
volume = "407",
pages = "26--36",
journal = "Molecular and Cellular Endocrinology",
issn = "0303-7207",
publisher = "Elsevier Ireland Ltd",

}

TY - JOUR

T1 - NELF knockout is associated with impaired pubertal development and subfertility

AU - Quaynor, Samuel D.

AU - Ko, Eun Kyung

AU - Chorich, Lynn P.

AU - Sullivan, Megan E.

AU - Demir, Durkadin

AU - Waller, Jennifer L

AU - Kim, Hyung Goo

AU - Cameron, Richard S

AU - Layman, Lawrence C

PY - 2015/5/5

Y1 - 2015/5/5

N2 - 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.

AB - 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.

KW - GnRH neuron migration

KW - Infertility

KW - NELF

KW - NSMF

KW - Nasal embryonic LHRH factor

UR - http://www.scopus.com/inward/record.url?scp=84924957566&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84924957566&partnerID=8YFLogxK

U2 - 10.1016/j.mce.2015.02.015

DO - 10.1016/j.mce.2015.02.015

M3 - Article

C2 - 25731822

AN - SCOPUS:84924957566

VL - 407

SP - 26

EP - 36

JO - Molecular and Cellular Endocrinology

JF - Molecular and Cellular Endocrinology

SN - 0303-7207

ER -