Characterization of the molecular mechanisms that govern anti-Müllerian hormone synthesis and activity.
AMH
TGF-β superfamily
anti-Müllerian hormone
folliculogenesis
ovary
protein engineering
Journal
FASEB journal : official publication of the Federation of American Societies for Experimental Biology
ISSN: 1530-6860
Titre abrégé: FASEB J
Pays: United States
ID NLM: 8804484
Informations de publication
Date de publication:
Jan 2024
Jan 2024
Historique:
revised:
30
11
2023
received:
02
07
2023
accepted:
04
12
2023
medline:
22
12
2023
pubmed:
22
12
2023
entrez:
22
12
2023
Statut:
ppublish
Résumé
The roles of anti-Müllerian hormone (AMH) continue to expand, from its discovery as a critical factor in sex determination, through its identification as a regulator of ovarian folliculogenesis, its use in fertility clinics as a measure of ovarian reserve, and its emerging role in hypothalamic-pituitary function. In light of these actions, AMH is considered an attractive therapeutic target to address diverse reproductive needs, including fertility preservation. Here, we set out to characterize the molecular mechanisms that govern AMH synthesis and activity. First, we enhanced the processing of the AMH precursor to >90% by introducing more efficient proprotein convertase cleavage sites (RKKR or ISSRKKRSVSS [SCUT]). Importantly, enhanced processing corresponded with a dramatic increase in secreted AMH activity. Next, based on species differences across the AMH type II receptor-binding interface, we generated a series of human AMH variants and assessed bioactivity. AMH
Identifiants
pubmed: 38133902
doi: 10.1096/fj.202301335RR
doi:
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Pagination
e23377Subventions
Organisme : DHAC | National Health and Medical Research Council (NHMRC)
ID : 2013284
Informations de copyright
© 2023 The Authors. The FASEB Journal published by Wiley Periodicals LLC on behalf of Federation of American Societies for Experimental Biology.
Références
Jost A, Gonse-Danysz P, Jacquot R. Studies on physiology of fetal hypophysis in rabbits and its relation to testicular function. J Physiol Paris. 1953;45:134-136.
Mullen RD, Behringer RR. Molecular genetics of Mullerian duct formation, regression and differentiation. Sex Dev. 2014;8:281-296.
Picard JY, Cate RL, Racine C, Josso N. The persistent Mullerian duct syndrome: an update based upon a personal experience of 157 cases. Sex Dev. 2017;11:109-125.
Rajpert-De Meyts E, Jorgensen N, Graem N, Muller J, Cate RL, Skakkebaek NE. Expression of anti-Mullerian hormone during normal and pathological gonadal development: association with differentiation of Sertoli and granulosa cells. J Clin Endocrinol Metab. 1999;84:3836-3844.
Munsterberg A, Lovellbadge R. Expression of the mouse anti-Mullerian hormone gene suggests a role in both male and female sexual-differentiation. Development. 1991;113:613-624.
Dewailly D, Andersen CY, Balen A, et al. The physiology and clinical utility of anti-Mullerian hormone in women. Hum Reprod Update. 2014;20:370-385.
Durlinger AL, Kramer P, Karels B, et al. Control of primordial follicle recruitment by anti-Mullerian hormone in the mouse ovary. Endocrinology. 1999;140:5789-5796.
Visser JA, Schipper I, Laven JS, Themmen AP. Anti-Mullerian hormone: an ovarian reserve marker in primary ovarian insufficiency. Nat Rev Endocrinol. 2012;8:331-341.
Xu J, Bishop CV, Lawson MS, Park BS, Xu F. Anti-Mullerian hormone promotes pre-antral follicle growth, but inhibits antral follicle maturation and dominant follicle selection in primates. Hum Reprod. 2016;31:1522-1530.
Xu J, Xu FH, Lawson MS, et al. Anti-Mullerian hormone is a survival factor and promotes the growth of rhesus macaque preantral follicles during matrix-free culture. Biol Reprod. 2018;98:197-207.
Visser JA, Themmen APN. Role of anti-Mullerian hormone and bone morphogenetic proteins in the regulation of FSH sensitivity. Mol Cell Endocrinol. 2014;382:460-465.
Durlinger ALL, Gruijters MJG, Kramer P, et al. Anti-Mullerian hormone attenuates the effects of FSH on follicle development in the mouse ovary. Endocrinology. 2001;142:4891-4899.
Pellatt L, Rice S, Dilaver N, et al. Anti-Mullerian hormone reduces follicle sensitivity to follicle-stimulating hormone in human granulosa cells. Fertil Steril. 2011;96:1246-1251.
Iwase A, Nakamura T, Osuka S, Takikawa S, Goto M, Kikkawa F. Anti-Mullerian hormone as a marker of ovarian reserve: what have we learned, and what should we know? Reprod Med Biol. 2016;15:127-136.
Victoria M, Labrosse J, Krief F, Cedrin-Durnerin I, Comtet M, Grynberg M. Anti Mullerian hormone: more than a biomarker of female reproductive function. J Gynecol Obstet Hum Reprod. 2019;48:19-24.
Pepinsky RB, Sinclair LK, Chow EP, et al. Proteolytic processing of Mullerian inhibiting substance produces a transforming growth factor-beta-like fragment. J Biol Chem. 1988;263:18961-18964.
Nachtigal MW, Ingraham HA. Bioactivation of Mullerian inhibiting substance during gonadal development by a kex2/subtilisin-like endoprotease. Proc Natl Acad Sci U S A. 1996;93:7711-7716.
di Clemente N, Jamin SP, Lugovskoy A, et al. Processing of anti-Mullerian hormone regulates receptor activation by a mechanism distinct from TGF-beta. Mol Endocrinol. 2010;24:2193-2206.
Kurian MS, Delacuesta RS, Waneck GL, Maclaughlin DT, Manganaro TF, Donahoe PK. Cleavage of Mullerian-inhibiting substance activates antiproliferative effects in-vivo. Clin Cancer Res. 1995;1:343-349.
Maclaughlin DT, Hudson PL, Graciano AL, et al. Mullerian duct regression and antiproliferative bioactivities of Mullerian inhibiting substance reside in its carboxy-terminal domain. Endocrinology. 1992;131:291-296.
Wilson CA, Diclemente N, Ehrenfels C, et al. Mullerian inhibiting substance requires its N-terminal domain for maintenance of biological-activity, a novel finding within the transforming growth-factor-beta superfamily. Mol Endocrinol. 1993;7:247-257.
Sengle G, Ono RN, Sasaki T, Sakai LY. Prodomains of transforming growth factor beta (TGF beta) superfamily members specify different functions extracellular matrix interactions and growth factor bioavailability. J Biol Chem. 2011;286:5087-5099.
Hart KN, Stocker WA, Nagykery NG, et al. Structure of AMH bound to AMHR2 provides insight into a unique signaling pair in the TGF-beta family. Proc Natl Acad Sci U S A. 2021;118:10.
Josso N, Clemente N. Transduction pathway of anti-Mullerian hormone, a sex-specific member of the TGF-beta family. Trends Endocrinol Metab. 2003;14:91-97.
Orvis GD, Jamin SP, Kwan KM, et al. Functional redundancy of TGF-beta family type receptors and receptor-smads in mediating anti-Mullerian hormone-induced Mullerian duct regression in the mouse. Biol Reprod. 2008;78:994-1001.
Meinsohn MC, Saatcioglu HD, Wei LA, et al. Single-cell sequencing reveals suppressive transcriptional programs regulated by MIS/AMH in neonatal ovaries. Proc Natl Acad Sci U S A. 2021;118:12.
Kano M, Sosulski AE, Zhang L, et al. AMH/MIS as a contraceptive that protects the ovarian reserve during chemotherapy. Proc Natl Acad Sci U S A. 2017;114:E1688-E1697.
Kalich-Philosoph L, Roness H, Carmely A, et al. Cyclophosphamide triggers follicle activation and “burnout”; AS101 prevents follicle loss and preserves fertility. Sci Transl Med. 2013;5:185ra162.
Roness H, Spector I, Leichtmann-Bardoogo Y, Savino AM, Dereh-Haim S, Meirow D. Pharmacological administration of recombinant human AMH rescues ovarian reserve and preserves fertility in a mouse model of chemotherapy, without interfering with anti-tumoural effects. J Assist Reprod Genet. 2019;36:1793-1803.
Sonigo C, Beau I, Grynberg M, Binart N. AMH prevents primordial ovarian follicle loss and fertility alteration in cyclophosphamide-treated mice. FASEB J. 2019;33:1278-1287.
Weenen C, Laven JSE, von Bergh ARM, et al. Anti-Mullerian hormone expression pattern in the human ovary: potential implications for initial and cyclic follicle recruitment. Mol Hum Reprod. 2004;10:77-83.
Duckert P, Brunak S, Blom N. Prediction of proprotein convertase cleavage sites. Protein Eng des Sel. 2004;17:107-112.
Vandenbergbakker CAM, Hagemeijer A, Frankenpostma EM, et al. Establishment and characterization of 7 ovarian-carcinoma cell-lines and one granulosa tumor-cell line-growth features and cytogenetics. Int J Cancer. 1993;53:613-620.
Zhang H, Vollmer M, De Geyter M, et al. Characterization of an immortalized human granulosa cell line (COV434). Mol Hum Reprod. 2000;6:146-153.
Karnezis AN, Chen SY, Chow C, et al. Re-assigning the histologic identities of COV434 and TOV-112D ovarian cancer cell lines. Gynecol Oncol. 2021;160:568-578.
Stocker WA, Walton KL, Richani D, et al. A variant of human growth differentiation factor-9 that improves oocyte developmental competence. J Biol Chem. 2020;295:7981-7991.
Jumper J, Evans R, Pritzel A, et al. Highly accurate protein structure prediction with AlphaFold. Nature. 2021;596:583-589.
Evans R, O'Neill M, Pritzel A, et al. Protein Complex Prediction with AlphaFold-Multimer. Cold Spring Harbor Laboratory Press, Cold Spring Harbor; 2022.
Case DA, Betz RM, Cerutti DS, et al. AMBER 2016. University of California; 2016.
Chen F, Liu H, Sun HY, et al. Assessing the performance of the MM/PBSA and MM/GBSA methods. 6. Capability to predict protein-protein binding free energies and re-rank binding poses generated by protein-protein docking. Phys Chem Chem Phys. 2016;18:22129-22139.
Walton KL, Makanji Y, Wilce MC, Chan KL, Robertson DM, Harrison CA. A common biosynthetic pathway governs the dimerization and secretion of inhibin and related transforming growth factor beta (TGF beta) ligands. J Biol Chem. 2009;284:9311-9320.
Walton KL, Makanji Y, Chen J, et al. Two distinct regions of latency-associated peptide coordinate stability of the latent transforming growth factor-beta 1 complex. J Biol Chem. 2010;285:17029-17037.
Goney MP, Wilce MCJ, Wilce JA, et al. Engineering the ovarian hormones inhibin a and inhibin B to enhance synthesis and activity. Endocrinology. 2020;161:bqaa099.
Hinck AP, Mueller TD, Springer TA. Structural biology and evolution of the TGF-beta family. Cold Spring Harb Perspect Biol. 2016;8:51.
Shi ML, Zhu JH, Wang R, et al. Latent TGF-beta structure and activation. Nature. 2011;474:343-370.
Pépin D, Hoang M, Nicolaou F, et al. An albumin leader sequence coupled with a cleavage site modification enhances the yield of recombinant C-terminal Mullerian inhibiting substance. Dent Tech. 2013;1:63-71.
Walton KL, Kelly EK, Johnson KE, Robertson DM, Stanton PG, Harrison CA. A novel, more efficient approach to generate bioactive inhibins. Endocrinology. 2016;157:2799-2809.
Hart KN, Pepin D, Czepnik M, Donahoe PK, Thompson TB. Mutational analysis of the putative anti-Mullerian hormone (AMH) binding interface on its type II receptor, AMHR2. Endocrinology. 2020;161:bqaa066.
Saremba S, Nickel J, Seher A, Kotzsch A, Sebald W, Mueller TD. Type I receptor binding of bone morphogenetic protein 6 is dependent on N-glycosylation of the ligand. FEBS J. 2008;275:172-183.
Goebel EJ, Hart KN, McCoy JC, Thompson TB. Structural biology of the TGF beta family. Exp Biol Med. 2019;244:1530-1546.
Jamin SP, Arango NA, Mishina Y, Hanks MC, Behringer RR. Requirement of Bmpr1a for Mullerian duct regression during male sexual development. Nat Genet. 2002;32:408-410.
Belville C, Jamin SP, Picard JY, Josso N, di Clemente N. Role of type I receptors for anti-Mullerian hormone in the SMAT-1 Sertoli cell line. Oncogene. 2005;24:4984-4992.
Sedes L, Leclerc A, Moindjie H, et al. Anti-Mullerian hormone recruits BMPR-IA in immature granulosa cells. PLoS One. 2013;8:13.
Allendorph GP, Vale WW, Choe S. Structure of the ternary signaling complex of a TGF-beta superfamily member. Proc Natl Acad Sci U S A. 2006;103:7643-7648.
Hoyos LR, Visser JA, McLuskey A, Chazenbalk GD, Grogan TR, Dumesic DA. Loss of anti-Mullerian hormone (AMH) immunoactivity due to a homozygous AMH gene variant rs10417628 in a woman with classical polycystic ovary syndrome (PCOS). Hum Reprod. 2020;35:2294-2302.
Harrison CA, Al-Musawi SL, Walton KL. Prodomains regulate the synthesis, extracellular localisation and activity of TGF-beta superfamily ligands. Growth Factors. 2011;29:174-186.
Cotton TR, Fischer G, Wang XL, et al. Structure of the human myostatin precursor and determinants of growth factor latency. EMBO J. 2018;37:367-383.
Wang XL, Fischer G, Hyvonen M. Structure and activation of pro-activin A. Nat Commun. 2016;7:11.
Mi LZ, Brown CT, Gao YJ, et al. Structure of bone morphogenetic protein 9 procomplex. Proc Natl Acad Sci U S A. 2015;112:3710-3715.
Meng L, McLuskey A, Dunaif A, Visser JA. Functional analysis of rare anti-Mullerian hormone protein-altering variants identified in women with PCOS. Mol Hum Reprod. 2023;29:10.
Cate RL, di Clemente N, Racine C, Groome NP, Pepinsky RB, Whitty A. The anti-Mullerian hormone prodomain is displaced from the hormone/prodomain complex upon bivalent binding to the hormone receptor. J Biol Chem. 2022;298:19.
Pankhurst MW, Chong YH, McLennan IS. Relative levels of the proprotein and cleavage-activated form of circulating human anti-Mullerian hormone are sexually dimorphic and variable during the life cycle. Physiol Rep. 2016;4:10.
Constam DB. Regulation of TGF beta and related signals by precursor processing. Semin Cell Dev Biol. 2014;32:85-97.
Howard JA, Hart KN, Thompson TB. Molecular mechanisms of AMH signaling. Front Endocrinol. 2022;13:9.
Simpson CM, Stanton PG, Walton KL, et al. Activation of latent human GDF9 by a single residue change (Gly391Arg) in the mature domain. Endocrinology. 2012;153:1301-1310.
Al-Musawi SL, Walton KL, Heath D, Simpson CM, Harrison CA. Species differences in the expression and activity of bone morphogenetic protein 15. Endocrinology. 2013;154:888-899.
Visser JA, Olaso R, Verhoef-Post M, Kramer P, Themmen APN, Ingraham HA. The serine/threonine transmembrane receptor ALK2 mediates Mullerian inhibiting substance signaling. Mol Endocrinol. 2001;15:936-945.
Clarke TR, Hoshiya Y, Yi SE, Liu XH, Lyons KM, Donahoe PK. Mullerian inhibiting substance signaling uses a bone morphogenetic protein (BMP)-like pathway mediated by ALK2 and induces Smad6 expression. Mol Endocrinol. 2001;15:946-959.
Gouedard L, Chen YG, Thevenet L, et al. Engagement of bone morphogenetic protein type IB receptor and SMAD1 signaling by anti-Mullerian hormone and its type II receptor. J Biol Chem. 2000;275:27973-27978.
Rodgers RJ, Abbott JA, Walters KA, Ledger WL. Translational physiology of anti-Mullerian hormone: clinical applications in female fertility preservation and cancer treatment. Front Endocrinol. 2021;12:14.