TGFBR3L is an inhibin B co-receptor that regulates female fertility

Emilie Brule; Ying Wang; Yining Li; Yeu Farn Lin; Xiang Zhou; Luisina Ongaro; Carlos A.I. Alonso; Evan R.S. Buddle; Alan L. Schneyer; Chang Hyeock Byeon; Cynthia S. Hinck; Natalia Mendelev; John P. Russell; Mitra Cowan; Ulrich Boehm; Frederique Ruf-Zamojski; Michel Zamojski; Cynthia L. Andoniadou; Stuart C. Sealfon; Craig A. Harrison; Kelly L. Walton; Andrew P. Hinck; Daniel J. Bernard

doi:10.1126/sciadv.abl4391

TGFBR3L is an inhibin B co-receptor that regulates female fertility

Emilie Brule, Ying Wang, Yining Li, Yeu Farn Lin, Xiang Zhou, Luisina Ongaro, Carlos A.I. Alonso, Evan R.S. Buddle, Alan L. Schneyer, Chang Hyeock Byeon, Cynthia S. Hinck, Natalia Mendelev, John P. Russell, Mitra Cowan, Ulrich Boehm, Frederique Ruf-Zamojski, Michel Zamojski, Cynthia L. Andoniadou, Stuart C. Sealfon, Craig A. HarrisonKelly L. Walton, Andrew P. Hinck, Daniel J. Bernard

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Abstract

Follicle-stimulating hormone (FSH), a key regulator of ovarian function, is often used in infertility treatment. Gonadal inhibins suppress FSH synthesis by pituitary gonadotrope cells. The TGFβ type III receptor, betaglycan, is required for inhibin A suppression of FSH. The inhibin B co-receptor was previously unknown. Here, we report that the gonadotrope-restricted transmembrane protein, TGFBR3L, is the elusive inhibin B co-receptor. TGFBR3L binds inhibin B but not other TGFβ family ligands. TGFBR3L knockdown or overexpression abrogates or confers inhibin B activity in cells. Female Tgfbr3l knockout mice exhibit increased FSH levels, ovarian follicle development, and litter sizes. In contrast, female mice lacking both TGFBR3L and betaglycan are infertile. TGFBR3L's function and cell-specific expression make it an attractive new target for the regulation of FSH and fertility.

Original language	English
Article number	eabl4391
Number of pages	16
Journal	Science Advances
Volume	7
Issue number	51
DOIs	https://doi.org/10.1126/sciadv.abl4391
Publication status	Published - Dec 2021

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Brule, E., Wang, Y., Li, Y., Lin, Y. F., Zhou, X., Ongaro, L., Alonso, C. A. I., Buddle, E. R. S., Schneyer, A. L., Byeon, C. H., Hinck, C. S., Mendelev, N., Russell, J. P., Cowan, M., Boehm, U., Ruf-Zamojski, F., Zamojski, M., Andoniadou, C. L., Sealfon, S. C., ... Bernard, D. J. (2021). TGFBR3L is an inhibin B co-receptor that regulates female fertility. Science Advances, 7(51), Article eabl4391. https://doi.org/10.1126/sciadv.abl4391

@article{da142f2d36344300a08b8ad826c7abe8,

title = "TGFBR3L is an inhibin B co-receptor that regulates female fertility",

abstract = "Follicle-stimulating hormone (FSH), a key regulator of ovarian function, is often used in infertility treatment. Gonadal inhibins suppress FSH synthesis by pituitary gonadotrope cells. The TGFβ type III receptor, betaglycan, is required for inhibin A suppression of FSH. The inhibin B co-receptor was previously unknown. Here, we report that the gonadotrope-restricted transmembrane protein, TGFBR3L, is the elusive inhibin B co-receptor. TGFBR3L binds inhibin B but not other TGFβ family ligands. TGFBR3L knockdown or overexpression abrogates or confers inhibin B activity in cells. Female Tgfbr3l knockout mice exhibit increased FSH levels, ovarian follicle development, and litter sizes. In contrast, female mice lacking both TGFBR3L and betaglycan are infertile. TGFBR3L's function and cell-specific expression make it an attractive new target for the regulation of FSH and fertility. ",

author = "Emilie Brule and Ying Wang and Yining Li and Lin, {Yeu Farn} and Xiang Zhou and Luisina Ongaro and Alonso, {Carlos A.I.} and Buddle, {Evan R.S.} and Schneyer, {Alan L.} and Byeon, {Chang Hyeock} and Hinck, {Cynthia S.} and Natalia Mendelev and Russell, {John P.} and Mitra Cowan and Ulrich Boehm and Frederique Ruf-Zamojski and Michel Zamojski and Andoniadou, {Cynthia L.} and Sealfon, {Stuart C.} and Harrison, {Craig A.} and Walton, {Kelly L.} and Hinck, {Andrew P.} and Bernard, {Daniel J.}",

note = "Funding Information: This work was supported by Canadian Institutes of Health Research project grant PJT-162343 (to D.J.B.), NIH grant GM58670 (to A.P.H.), NIH grant DK46943 (to S.C.S.), Medical Research Council MR/T012153/1 (to C.L.A.), Natural Sciences and Engineering Research Council of Canada Doctoral Graduate Scholarship (to E.B.), Canadian Institutes of Health Research Master's Graduate Scholarship (to Y.-F.L.), and McGill University James Frosst Award (to Y.-F.L.). Publisher Copyright: Copyright {\textcopyright} 2021 The Authors, some rights reserved.",

year = "2021",

month = dec,

doi = "10.1126/sciadv.abl4391",

language = "English",

volume = "7",

journal = "Science Advances",

issn = "2375-2548",

publisher = "American Association for the Advancement of Science (AAAS)",

number = "51",

}

Brule, E, Wang, Y, Li, Y, Lin, YF, Zhou, X, Ongaro, L, Alonso, CAI, Buddle, ERS, Schneyer, AL, Byeon, CH, Hinck, CS, Mendelev, N, Russell, JP, Cowan, M, Boehm, U, Ruf-Zamojski, F, Zamojski, M, Andoniadou, CL, Sealfon, SC, Harrison, CA , Walton, KL, Hinck, AP & Bernard, DJ 2021, 'TGFBR3L is an inhibin B co-receptor that regulates female fertility', Science Advances, vol. 7, no. 51, eabl4391. https://doi.org/10.1126/sciadv.abl4391

TY - JOUR

T1 - TGFBR3L is an inhibin B co-receptor that regulates female fertility

AU - Brule, Emilie

AU - Wang, Ying

AU - Li, Yining

AU - Lin, Yeu Farn

AU - Zhou, Xiang

AU - Ongaro, Luisina

AU - Alonso, Carlos A.I.

AU - Buddle, Evan R.S.

AU - Schneyer, Alan L.

AU - Byeon, Chang Hyeock

AU - Hinck, Cynthia S.

AU - Mendelev, Natalia

AU - Russell, John P.

AU - Cowan, Mitra

AU - Boehm, Ulrich

AU - Ruf-Zamojski, Frederique

AU - Zamojski, Michel

AU - Andoniadou, Cynthia L.

AU - Sealfon, Stuart C.

AU - Harrison, Craig A.

AU - Walton, Kelly L.

AU - Hinck, Andrew P.

AU - Bernard, Daniel J.

N1 - Funding Information: This work was supported by Canadian Institutes of Health Research project grant PJT-162343 (to D.J.B.), NIH grant GM58670 (to A.P.H.), NIH grant DK46943 (to S.C.S.), Medical Research Council MR/T012153/1 (to C.L.A.), Natural Sciences and Engineering Research Council of Canada Doctoral Graduate Scholarship (to E.B.), Canadian Institutes of Health Research Master's Graduate Scholarship (to Y.-F.L.), and McGill University James Frosst Award (to Y.-F.L.). Publisher Copyright: Copyright © 2021 The Authors, some rights reserved.

PY - 2021/12

Y1 - 2021/12

N2 - Follicle-stimulating hormone (FSH), a key regulator of ovarian function, is often used in infertility treatment. Gonadal inhibins suppress FSH synthesis by pituitary gonadotrope cells. The TGFβ type III receptor, betaglycan, is required for inhibin A suppression of FSH. The inhibin B co-receptor was previously unknown. Here, we report that the gonadotrope-restricted transmembrane protein, TGFBR3L, is the elusive inhibin B co-receptor. TGFBR3L binds inhibin B but not other TGFβ family ligands. TGFBR3L knockdown or overexpression abrogates or confers inhibin B activity in cells. Female Tgfbr3l knockout mice exhibit increased FSH levels, ovarian follicle development, and litter sizes. In contrast, female mice lacking both TGFBR3L and betaglycan are infertile. TGFBR3L's function and cell-specific expression make it an attractive new target for the regulation of FSH and fertility.

AB - Follicle-stimulating hormone (FSH), a key regulator of ovarian function, is often used in infertility treatment. Gonadal inhibins suppress FSH synthesis by pituitary gonadotrope cells. The TGFβ type III receptor, betaglycan, is required for inhibin A suppression of FSH. The inhibin B co-receptor was previously unknown. Here, we report that the gonadotrope-restricted transmembrane protein, TGFBR3L, is the elusive inhibin B co-receptor. TGFBR3L binds inhibin B but not other TGFβ family ligands. TGFBR3L knockdown or overexpression abrogates or confers inhibin B activity in cells. Female Tgfbr3l knockout mice exhibit increased FSH levels, ovarian follicle development, and litter sizes. In contrast, female mice lacking both TGFBR3L and betaglycan are infertile. TGFBR3L's function and cell-specific expression make it an attractive new target for the regulation of FSH and fertility.

UR - http://www.scopus.com/inward/record.url?scp=85122005084&partnerID=8YFLogxK

U2 - 10.1126/sciadv.abl4391

DO - 10.1126/sciadv.abl4391

M3 - Article

C2 - 34910520

AN - SCOPUS:85122005084

SN - 2375-2548

VL - 7

JO - Science Advances

JF - Science Advances

IS - 51

M1 - eabl4391

ER -

TGFBR3L is an inhibin B co-receptor that regulates female fertility

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