Murine inhibin alpha-subunit haploinsufficiency causes transient abnormalities in prepubertal testis development followed by adult testicular decline

Catherine Mary Itman, Amanda Bielanowicz, Hoey Goh, Queenie C Y Lee, Alex J Fulcher, Sarah C Moody, James C G Doery, Jacinta Martin, Sarah Eyre, Mark P Hedger, Katherine A L Loveland

Research output: Contribution to journalArticleResearchpeer-review

Abstract

Activin production and signaling must be strictly regulated for normal testis development and function. Inhibins are potent activin inhibitors; mice lacking the inhibin-alpha gene (Inha-/- mice) cannot make inhibin and consequently have highly elevated activin and FSH serum concentrations and excessive activin signaling, resulting in somatic gonadal tumors and infertility. Dose-dependent effects of activin in testicular biology have been widely reported; hence, we hypothesized that male mice lacking one copy of the Inha gene would produce less inhibin and have an abnormal reproductive phenotype. To test this, we compared hormone concentrations, testis development, and sperm production in Inha+/+ and Inha+/- mice. Serum and testicular inhibin-alpha concentrations in adult Inha+/- mice were approximately 33 lower than wild type, whereas activin A, activin B, FSH, LH, and T were normal. Sixteen-day-old Inha+/- mice had a mixed phenotype, with tubules containing extensive germ cell depletion juxtaposed to tubules with advanced Sertoli and germ cell development. This abnormal phenotype resolved by day 28. By 8 weeks, Inha+/- testes were 11 larger than wild type and supported 44 greater daily sperm production. By 26 weeks of age, Inha+/- testes had distinct abnormalities. Although still fertile, Inha+/- mice had a 27 reduction in spermatogenic efficiency, a greater proportion of S-phase Sertoli cells and lower Leydig cell CYP11A1 expression. This study is the first to identify an intratesticular role for inhibin/inhibin-alpha subunit, demonstrating that a threshold level of this protein is required for normal testis development and to sustain adult somatic testicular cell function.
Original languageEnglish
Pages (from-to)2254 - 2268
Number of pages15
JournalEndocrinology
Volume156
Issue number6
DOIs
Publication statusPublished - 2015

Cite this

Itman, Catherine Mary ; Bielanowicz, Amanda ; Goh, Hoey ; Lee, Queenie C Y ; Fulcher, Alex J ; Moody, Sarah C ; Doery, James C G ; Martin, Jacinta ; Eyre, Sarah ; Hedger, Mark P ; Loveland, Katherine A L. / Murine inhibin alpha-subunit haploinsufficiency causes transient abnormalities in prepubertal testis development followed by adult testicular decline. In: Endocrinology. 2015 ; Vol. 156, No. 6. pp. 2254 - 2268.
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title = "Murine inhibin alpha-subunit haploinsufficiency causes transient abnormalities in prepubertal testis development followed by adult testicular decline",
abstract = "Activin production and signaling must be strictly regulated for normal testis development and function. Inhibins are potent activin inhibitors; mice lacking the inhibin-alpha gene (Inha-/- mice) cannot make inhibin and consequently have highly elevated activin and FSH serum concentrations and excessive activin signaling, resulting in somatic gonadal tumors and infertility. Dose-dependent effects of activin in testicular biology have been widely reported; hence, we hypothesized that male mice lacking one copy of the Inha gene would produce less inhibin and have an abnormal reproductive phenotype. To test this, we compared hormone concentrations, testis development, and sperm production in Inha+/+ and Inha+/- mice. Serum and testicular inhibin-alpha concentrations in adult Inha+/- mice were approximately 33 lower than wild type, whereas activin A, activin B, FSH, LH, and T were normal. Sixteen-day-old Inha+/- mice had a mixed phenotype, with tubules containing extensive germ cell depletion juxtaposed to tubules with advanced Sertoli and germ cell development. This abnormal phenotype resolved by day 28. By 8 weeks, Inha+/- testes were 11 larger than wild type and supported 44 greater daily sperm production. By 26 weeks of age, Inha+/- testes had distinct abnormalities. Although still fertile, Inha+/- mice had a 27 reduction in spermatogenic efficiency, a greater proportion of S-phase Sertoli cells and lower Leydig cell CYP11A1 expression. This study is the first to identify an intratesticular role for inhibin/inhibin-alpha subunit, demonstrating that a threshold level of this protein is required for normal testis development and to sustain adult somatic testicular cell function.",
author = "Itman, {Catherine Mary} and Amanda Bielanowicz and Hoey Goh and Lee, {Queenie C Y} and Fulcher, {Alex J} and Moody, {Sarah C} and Doery, {James C G} and Jacinta Martin and Sarah Eyre and Hedger, {Mark P} and Loveland, {Katherine A L}",
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Murine inhibin alpha-subunit haploinsufficiency causes transient abnormalities in prepubertal testis development followed by adult testicular decline. / Itman, Catherine Mary; Bielanowicz, Amanda; Goh, Hoey; Lee, Queenie C Y; Fulcher, Alex J; Moody, Sarah C; Doery, James C G; Martin, Jacinta; Eyre, Sarah; Hedger, Mark P; Loveland, Katherine A L.

In: Endocrinology, Vol. 156, No. 6, 2015, p. 2254 - 2268.

Research output: Contribution to journalArticleResearchpeer-review

TY - JOUR

T1 - Murine inhibin alpha-subunit haploinsufficiency causes transient abnormalities in prepubertal testis development followed by adult testicular decline

AU - Itman, Catherine Mary

AU - Bielanowicz, Amanda

AU - Goh, Hoey

AU - Lee, Queenie C Y

AU - Fulcher, Alex J

AU - Moody, Sarah C

AU - Doery, James C G

AU - Martin, Jacinta

AU - Eyre, Sarah

AU - Hedger, Mark P

AU - Loveland, Katherine A L

PY - 2015

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N2 - Activin production and signaling must be strictly regulated for normal testis development and function. Inhibins are potent activin inhibitors; mice lacking the inhibin-alpha gene (Inha-/- mice) cannot make inhibin and consequently have highly elevated activin and FSH serum concentrations and excessive activin signaling, resulting in somatic gonadal tumors and infertility. Dose-dependent effects of activin in testicular biology have been widely reported; hence, we hypothesized that male mice lacking one copy of the Inha gene would produce less inhibin and have an abnormal reproductive phenotype. To test this, we compared hormone concentrations, testis development, and sperm production in Inha+/+ and Inha+/- mice. Serum and testicular inhibin-alpha concentrations in adult Inha+/- mice were approximately 33 lower than wild type, whereas activin A, activin B, FSH, LH, and T were normal. Sixteen-day-old Inha+/- mice had a mixed phenotype, with tubules containing extensive germ cell depletion juxtaposed to tubules with advanced Sertoli and germ cell development. This abnormal phenotype resolved by day 28. By 8 weeks, Inha+/- testes were 11 larger than wild type and supported 44 greater daily sperm production. By 26 weeks of age, Inha+/- testes had distinct abnormalities. Although still fertile, Inha+/- mice had a 27 reduction in spermatogenic efficiency, a greater proportion of S-phase Sertoli cells and lower Leydig cell CYP11A1 expression. This study is the first to identify an intratesticular role for inhibin/inhibin-alpha subunit, demonstrating that a threshold level of this protein is required for normal testis development and to sustain adult somatic testicular cell function.

AB - Activin production and signaling must be strictly regulated for normal testis development and function. Inhibins are potent activin inhibitors; mice lacking the inhibin-alpha gene (Inha-/- mice) cannot make inhibin and consequently have highly elevated activin and FSH serum concentrations and excessive activin signaling, resulting in somatic gonadal tumors and infertility. Dose-dependent effects of activin in testicular biology have been widely reported; hence, we hypothesized that male mice lacking one copy of the Inha gene would produce less inhibin and have an abnormal reproductive phenotype. To test this, we compared hormone concentrations, testis development, and sperm production in Inha+/+ and Inha+/- mice. Serum and testicular inhibin-alpha concentrations in adult Inha+/- mice were approximately 33 lower than wild type, whereas activin A, activin B, FSH, LH, and T were normal. Sixteen-day-old Inha+/- mice had a mixed phenotype, with tubules containing extensive germ cell depletion juxtaposed to tubules with advanced Sertoli and germ cell development. This abnormal phenotype resolved by day 28. By 8 weeks, Inha+/- testes were 11 larger than wild type and supported 44 greater daily sperm production. By 26 weeks of age, Inha+/- testes had distinct abnormalities. Although still fertile, Inha+/- mice had a 27 reduction in spermatogenic efficiency, a greater proportion of S-phase Sertoli cells and lower Leydig cell CYP11A1 expression. This study is the first to identify an intratesticular role for inhibin/inhibin-alpha subunit, demonstrating that a threshold level of this protein is required for normal testis development and to sustain adult somatic testicular cell function.

UR - http://press.endocrine.org/doi/full/10.1210/en.2014-1555

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DO - 10.1210/en.2014-1555

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