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Article: Structural Basis of Non-Latent Signaling by the Anti-Müllerian Hormone Procomplex.

Howard, James A / Hok, Lucija / Cate, Richard L / Sanford, Nathaniel J / Hart, Kaitlin N / Leach, Edmund Ae / Bruening, Alena S / Pépin, David / Donahoe, Patricia K / Thompson, Thomas B

bioRxiv : the preprint server for biology

2024

Abstract: Most TGFβ family ligands exist as procomplexes consisting of a prodomain noncovalently bound to a growth factor (GF); Whereas some prodomains confer latency, the Anti-Müllerian Hormone (AMH) prodomain maintains a remarkably high affinity for the GF yet ... ...

Abstract	Most TGFβ family ligands exist as procomplexes consisting of a prodomain noncovalently bound to a growth factor (GF); Whereas some prodomains confer latency, the Anti-Müllerian Hormone (AMH) prodomain maintains a remarkably high affinity for the GF yet remains active. Using single particle EM methods, we show the AMH prodomain consists of two subdomains: a vestigial TGFβ prodomain-like fold and a novel, helical bundle GF-binding domain, the result of an exon insertion 450 million years ago, that engages both receptor epitopes. When associated with the prodomain, the AMH GF is distorted into a strained, open conformation whose closure upon bivalent binding of AMHR2 displaces the prodomain through a conformational shift mechanism to allow for signaling.
Language	English
Publishing date	2024-04-01
Publishing country	United States
Document type	Preprint
DOI	10.1101/2024.04.01.587627
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Article: FOXP1

Pendleton, Katherine E / Hernandez-Garcia, Andres / Lyu, Jennifer M / Campbell, Ian M / Shaw, Chad A / Vogt, Julie / High, Frances A / Donahoe, Patricia K / Chung, Wendy K / Scott, Daryl A

Journal of pediatric genetics

2023 Volume 13, Issue 1, Page(s) 29–34

Abstract: ... ...

Abstract	FOXP1
Language	English
Publishing date	2023-03-28
Publishing country	Germany
Document type	Journal Article
ISSN	2146-4596
ISSN	2146-4596
DOI	10.1055/s-0043-1767731
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Article ; Online: Müllerian inhibiting substance/anti-Müllerian hormone as a fertility preservation agent.

Pépin, David / Sabatini, Mary E / Donahoe, Patricia K

Current opinion in endocrinology, diabetes, and obesity

2018 Volume 25, Issue 6, Page(s) 399–405

Abstract: Purpose of review: The nascent field of oncofertility is quickly gaining traction as novel experimental treatments are being developed, driving a renewed interest in Müllerian inhibiting substance (MIS) as an ovarian fertoprotectant.: Recent findings!# ...

Abstract	Purpose of review: The nascent field of oncofertility is quickly gaining traction as novel experimental treatments are being developed, driving a renewed interest in Müllerian inhibiting substance (MIS) as an ovarian fertoprotectant. Recent findings: MIS is unique in its mechanisms of ovarian protection by virtue of acting directly on granulosa cells of primordial follicles and for being a benign reproductive hormone, with few side effects. We will explore in this review how it may be utilized to protect the ovary from chemotherapy, or to enhance ovarian tissue cryopreservation therapy. We will also examine potential mechanisms of action of MIS across multiple cell types, as well as current limitations in our understanding of the pharmacology of recombinant MIS. Summary: The usefulness of MIS as a fertoprotectant may be dependent on the mechanisms of gonadotoxicity of each chemotherapeutic. Further investigation is needed to determine how to best deliver and combine MIS treatment to existing fertility management strategies.
MeSH term(s)	Anti-Mullerian Hormone/physiology ; Anti-Mullerian Hormone/therapeutic use ; Cryopreservation/methods ; Female ; Fertility Agents, Female/therapeutic use ; Fertility Preservation/methods ; Granulosa Cells/drug effects ; Granulosa Cells/physiology ; Humans ; Ovarian Follicle/drug effects ; Ovarian Follicle/physiology ; Ovary
Chemical Substances	Fertility Agents, Female ; Anti-Mullerian Hormone (80497-65-0)
Language	English
Publishing date	2018-10-15
Publishing country	England
Document type	Journal Article ; Research Support, Non-U.S. Gov't ; Review
ZDB-ID	2272017-0
ISSN	1752-2978 ; 1752-296X
ISSN (online)	1752-2978
ISSN	1752-296X
DOI	10.1097/MED.0000000000000442
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Article ; Online: Mutational Analysis of the Putative Anti-Müllerian Hormone (AMH) Binding Interface on its Type II Receptor, AMHR2.

Hart, Kaitlin N / Pépin, David / Czepnik, Magdalena / Donahoe, Patricia K / Thompson, Thomas B

Endocrinology

2020 Volume 161, Issue 7

Abstract: Anti-Müllerian hormone (AMH) or Müllerian inhibiting substance is a unique member of the TGF-β family responsible for development and differentiation of the reproductive system. AMH signals through its own dedicated type II receptor, anti-Müllerian ... ...

Abstract	Anti-Müllerian hormone (AMH) or Müllerian inhibiting substance is a unique member of the TGF-β family responsible for development and differentiation of the reproductive system. AMH signals through its own dedicated type II receptor, anti-Müllerian hormone receptor type II (AMHR2), providing an exclusive ligand-receptor pair within the broader TGF-β family. In this study, we used previous structural information to derive a model of AMH bound to AMHR2 to guide mutagenesis studies to identify receptor residues important for AMH signaling. Nonconserved mutations were introduced in AMHR2 and characterized in an AMH-responsive cell-based luciferase assay and native PAGE. Collectively, our results identified several residues important for AMH signaling within the putative ligand binding interface of AMHR2. Our results show that AMH engages AMHR2 at a similar interface to how activin and BMP class ligands bind the type II receptor, ACVR2B; however, there are significant molecular differences at the ligand interface of these 2 receptors, where ACVR2B is mostly hydrophobic and AMHR2 is predominately charged. Overall, this study shows that although the location of ligand binding on the receptor is similar to ACVR2A, ACVR2B, and BMPR2; AMHR2 uses unique ligand-receptor interactions to impart specificity for AMH.
MeSH term(s)	Activin Receptors, Type II/chemistry ; Activin Receptors, Type II/metabolism ; Anti-Mullerian Hormone/metabolism ; Disorder of Sex Development, 46,XY/genetics ; HEK293 Cells ; Humans ; Mutagenesis, Site-Directed ; Receptors, Peptide/chemistry ; Receptors, Peptide/genetics ; Receptors, Peptide/metabolism ; Receptors, Transforming Growth Factor beta/chemistry ; Receptors, Transforming Growth Factor beta/genetics ; Receptors, Transforming Growth Factor beta/metabolism
Chemical Substances	Receptors, Peptide ; Receptors, Transforming Growth Factor beta ; anti-Mullerian hormone receptor ; Anti-Mullerian Hormone (80497-65-0) ; ACVR2B protein, human (EC 2.7.11.30) ; Activin Receptors, Type II (EC 2.7.11.30)
Language	English
Publishing date	2020-05-14
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't ; Research Support, U.S. Gov't, Non-P.H.S.
ZDB-ID	427856-2
ISSN	1945-7170 ; 0013-7227
ISSN (online)	1945-7170
ISSN	0013-7227
DOI	10.1210/endocr/bqaa066
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Article ; Online: A pediatric surgeon retools in genetics and genomics to study congenital diaphragmatic hernia.

Donahoe, Patricia K

Journal of pediatric surgery

2008 Volume 44, Issue 2, Page(s) 307–311

Abstract: Prof. Donahoe outlines her career-long interest in congenital diaphragmatic hernia and how this has ...

Abstract	Prof. Donahoe outlines her career-long interest in congenital diaphragmatic hernia and how this has led to her current investigations into its etiology and possible treatment using gene probes.
MeSH term(s)	Child ; General Surgery ; Genomics ; Hernia, Diaphragmatic/genetics ; Hernias, Diaphragmatic, Congenital ; Humans ; Pediatrics
Language	English
Publishing date	2008-02-07
Publishing country	United States
Document type	Lecture
ZDB-ID	80165-3
ISSN	1531-5037 ; 0022-3468
ISSN (online)	1531-5037
ISSN	0022-3468
DOI	10.1016/j.jpedsurg.2008.10.077
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Article ; Online: A Tracheal Aspirate-derived Airway Basal Cell Model Reveals a Proinflammatory Epithelial Defect in Congenital Diaphragmatic Hernia.

Wagner, Richard / Amonkar, Gaurang M / Wang, Wei / Shui, Jessica E / Bankoti, Kamakshi / Tse, Wai Hei / High, Frances A / Zalieckas, Jill M / Buchmiller, Terry L / Zani, Augusto / Keijzer, Richard / Donahoe, Patricia K / Lerou, Paul H / Ai, Xingbin

American journal of respiratory and critical care medicine

2022 Volume 207, Issue 9, Page(s) 1214–1226

Abstract: Rationale: ...

Abstract	Rationale:
MeSH term(s)	Infant, Newborn ; Rats ; Humans ; Animals ; Hernias, Diaphragmatic, Congenital ; NF-kappa B ; Rats, Sprague-Dawley ; Phenyl Ethers ; Lung/pathology ; Disease Models, Animal
Chemical Substances	nitrofen (N71UYG034A) ; NF-kappa B ; Phenyl Ethers
Language	English
Publishing date	2022-10-10
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ZDB-ID	1180953-x
ISSN	1535-4970 ; 0003-0805 ; 1073-449X
ISSN (online)	1535-4970
ISSN	0003-0805 ; 1073-449X
DOI	10.1164/rccm.202205-0953OC
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Article ; Online: Cancer-associated mesothelial cells are regulated by the anti-Müllerian hormone axis.

Chauvin, M / Meinsohn, M-C / Dasari, S / May, P / Iyer, S / Nguyen, N M P / Oliva, E / Lucchini, Z / Nagykery, N / Kashiwagi, A / Mishra, R / Maser, R / Wells, J / Bult, C J / Mitra, A K / Donahoe, Patricia K / Pépin, D

Cell reports

2023 Volume 42, Issue 7, Page(s) 112730

Abstract: Cancer-associated mesothelial cells (CAMCs) in the tumor microenvironment are thought to promote growth and immune evasion. We find that, in mouse and human ovarian tumors, cancer cells express anti-Müllerian hormone (AMH) while CAMCs express its ... ...

Abstract	Cancer-associated mesothelial cells (CAMCs) in the tumor microenvironment are thought to promote growth and immune evasion. We find that, in mouse and human ovarian tumors, cancer cells express anti-Müllerian hormone (AMH) while CAMCs express its receptor AMHR2, suggesting a paracrine axis. Factors secreted by cancer cells induce AMHR2 expression during their reprogramming into CAMCs in mouse and human in vitro models. Overexpression of AMHR2 in the Met5a mesothelial cell line is sufficient to induce expression of immunosuppressive cytokines and growth factors that stimulate ovarian cancer cell growth in an AMH-dependent way. Finally, syngeneic cancer cells implanted in transgenic mice with Amhr2
MeSH term(s)	Female ; Humans ; Animals ; Mice ; Anti-Mullerian Hormone/genetics ; Ovarian Neoplasms/genetics ; Peptide Hormones ; Mice, Transgenic ; Receptors, Transforming Growth Factor beta/metabolism ; Tumor Microenvironment
Chemical Substances	Anti-Mullerian Hormone (80497-65-0) ; Peptide Hormones ; Receptors, Transforming Growth Factor beta
Language	English
Publishing date	2023-07-14
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't ; Research Support, U.S. Gov't, Non-P.H.S.
ZDB-ID	2649101-1
ISSN	2211-1247 ; 2211-1247
ISSN (online)	2211-1247
ISSN	2211-1247
DOI	10.1016/j.celrep.2023.112730
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Article ; Online: The mandate for innovation in pediatric surgery; creating the environment for success, parity, and excellence.

Donahoe, Patricia K

Journal of pediatric surgery

2007 Volume 43, Issue 1, Page(s) 1–7

MeSH term(s)	Attitude of Health Personnel ; Clinical Competence ; Diffusion of Innovation ; Education, Medical, Graduate ; General Surgery/education ; General Surgery/ethics ; General Surgery/standards ; Humans ; Interprofessional Relations ; Molecular Biology/standards ; Pediatrics/education ; Pediatrics/ethics ; Pediatrics/standards ; Practice Patterns, Physicians' ; Quality of Health Care ; Safety Management ; United States
Language	English
Publishing date	2007-11-04
Publishing country	United States
Document type	Address
ZDB-ID	80165-3
ISSN	1531-5037 ; 0022-3468
ISSN (online)	1531-5037
ISSN	0022-3468
DOI	10.1016/j.jpedsurg.2007.09.008
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Article ; Online: Structure of AMH bound to AMHR2 provides insight into a unique signaling pair in the TGF-β family.

Hart, Kaitlin N / Stocker, William A / Nagykery, Nicholas G / Walton, Kelly L / Harrison, Craig A / Donahoe, Patricia K / Pépin, David / Thompson, Thomas B

Proceedings of the National Academy of Sciences of the United States of America

2021 Volume 118, Issue 26

Abstract: Anti-Müllerian hormone (AMH), or Müllerian-inhibiting substance, is a protein hormone that promotes Müllerian duct regression during male fetal sexual differentiation and regulation of folliculogenesis in women. AMH is a member of the transforming growth ...

Abstract	Anti-Müllerian hormone (AMH), or Müllerian-inhibiting substance, is a protein hormone that promotes Müllerian duct regression during male fetal sexual differentiation and regulation of folliculogenesis in women. AMH is a member of the transforming growth factor beta (TGF-β) family, which has evolved to signal through its own dedicated type II receptor, AMH receptor type II (AMHR2). Structures of other TGF-β family members have revealed how ligands infer specificity for their cognate receptors; however, it is unknown how AMH binds AMHR2 at the molecular level. Therefore, in this study, we solved the X-ray crystal structure of AMH bound to the extracellular domain of AMHR2 to a resolution of 2.6Å. The structure reveals that while AMH binds AMHR2 in a similar location to Activin and BMP ligand binding to their type II receptors, differences in both AMH and AMHR2 account for a highly specific interaction. Furthermore, using an AMH responsive cell-based luciferase assay, we show that a conformation in finger 1 of AMHR2 and a salt bridge formed by K534 on AMH and D81/E84 of AMHR2 are key to the AMH/AMHR2 interaction. Overall, our study highlights how AMH engages AMHR2 using a modified paradigm of receptor binding facilitated by modifications to the three-finger toxin fold of AMHR2. Furthermore, understanding these elements contributing to the specificity of binding will help in the design of agonists or antagonists or the selection of antibody therapies.
MeSH term(s)	Activins/chemistry ; Amino Acid Sequence ; Anti-Mullerian Hormone/chemistry ; Anti-Mullerian Hormone/metabolism ; Bone Morphogenetic Proteins/chemistry ; Crystallography, X-Ray ; Models, Molecular ; Receptors, Peptide/chemistry ; Receptors, Peptide/metabolism ; Receptors, Transforming Growth Factor beta/chemistry ; Receptors, Transforming Growth Factor beta/metabolism ; Signal Transduction ; Structural Homology, Protein ; Transforming Growth Factor beta/metabolism
Chemical Substances	Bone Morphogenetic Proteins ; Receptors, Peptide ; Receptors, Transforming Growth Factor beta ; Transforming Growth Factor beta ; anti-Mullerian hormone receptor ; Activins (104625-48-1) ; Anti-Mullerian Hormone (80497-65-0)
Language	English
Publishing date	2021-06-19
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ZDB-ID	209104-5
ISSN	1091-6490 ; 0027-8424
ISSN (online)	1091-6490
ISSN	0027-8424
DOI	10.1073/pnas.2104809118
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Article ; Online: Cross-country analysis of contextual factors and implementation strategies in under-5 mortality reduction in six low- and middle-income countries 2000-2015.

Binagwaho, Agnes / VanderZanden, Amelia / Garcia, Patricia J / Huda, Fauzia Akhter / Maskey, Mahesh / Sall, Mohamadou / Sayinzoga, Felix / Subedi, Raj Kumar / Teklu, Alula M / Donahoe, Kateri / Frisch, Miriam / Ntawukuriryayo, Jovial Thomas / Udoh, Kelechi / Hirschhorn, Lisa R

BMC pediatrics

2024 Volume 23, Issue Suppl 1, Page(s) 652

Abstract: Background: The Exemplars in Under-5 Mortality (U5M) was a multiple cases study of how six low- and middle-income countries (LMICs), Bangladesh, Ethiopia, Nepal, Peru, Rwanda, and Senegal, implemented health system-delivered evidence-based interventions ...

Abstract	Background: The Exemplars in Under-5 Mortality (U5M) was a multiple cases study of how six low- and middle-income countries (LMICs), Bangladesh, Ethiopia, Nepal, Peru, Rwanda, and Senegal, implemented health system-delivered evidence-based interventions (EBIs) to reduce U5M between 2000 and 2015 more effectively than others in their regions or with similar economic growth. Using implementation research, we conducted a cross-country analysis to compare decision-making pathways for how these countries chose, implemented, and adapted strategies for health system-delivered EBIs that mitigated or leveraged contextual factors to improve implementation outcomes in reducing amenable U5M. Methods: The cross-country analysis was based on the hybrid mixed methods implementation research framework used to inform the country case studies. The framework included a common pathway of Exploration, Preparation, Implementation, Adaptation, and Sustainment (EPIAS). From the existing case studies, we extracted contextual factors which were barriers, facilitators, or determinants of strategic decisions; strategies to implement EBIs; and implementation outcomes including acceptability and coverage. We identified common factors and strategies shared by countries, and individual approaches used by countries reflecting differences in contextual factors and goals. Results: We found the six countries implemented many of the same EBIs, often using similar strategies with adaptations to local context and disease burden. Common implementation strategies included use of data by decision-makers to identify problems and prioritize EBIs, determine implementation strategies and their adaptation, and measure outcomes; leveraging existing primary healthcare systems; and community and stakeholder engagement. We also found common facilitators included culture of donor and partner coordination and culture and capacity of data use, while common barriers included geography and culture and beliefs. We found evidence for achieving implementation outcomes in many countries and EBIs including acceptability, coverage, equity, and sustainability. Discussion: We found all six countries used a common pathway to implementation with a number of strategies common across EBIs and countries which contributed to progress, either despite contextual barriers or by leveraging facilitators. The transferable knowledge from this cross-country study can be used by other countries to more effectively implement EBIs known to reduce amenable U5M and contribute to strengthening health system delivery now and in the future.
MeSH term(s)	Humans ; Developing Countries ; Delivery of Health Care ; Peru ; Bangladesh ; Nepal
Language	English
Publishing date	2024-02-28
Publishing country	England
Document type	Journal Article
ZDB-ID	2041342-7
ISSN	1471-2431 ; 1471-2431
ISSN (online)	1471-2431
ISSN	1471-2431
DOI	10.1186/s12887-023-03906-5
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