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Scientist Emeritus: Maria L. Dufau M.D., Ph.D.

Positions at NIH

  • 1970-1975: Visiting Scientist, NICHD
  • 1975-1979: Senior Investigator, Endocrinology & Reproduction Research Branch, NICHD
  • 1979-2022: Senior Investigator & Chief, Section on Molecular Endocrinology, NICHD

Biography

Maria L. Dufau led the Section on Molecular Endocrinology, NICHD, NIH until her retirement in November of 2022 after more than 52 years of service. In this capacity, she directed a multidisciplinary research program on the regulation of luteinizing hormone (LH) and human chorionic gonadotropin (hCG) and prolactin receptors (LHR, PRLR), gene transcription and expression, as well as the identification, functional characterization, and regulation of genes that participate in the control of gonadal function. She received her M.D. and Ph.D. from the University of Cuyo in Mendoza, Argentina. She completed her clinical and research training at Harvard institutions under a Rockefeller Fellowship Award, in the Department of Medicine at Mass. General Hospital and the Department of Biological Chemistry at the Boston Lying-Inn. Afterwards, she spent a year as a clinical research scientist at the Institute of Clinical Research, Montreal, Canada; was a lecturer at the Department of Medicine at Prince Henry’s Hospital at Monash University, Melbourne, Australia; and subsequently spent a year sabbatical in the Department of Pediatrics at Cornell Medical School and New York Hospital, NY.             

Dr. Dufau joined NICHD in 1970 as a visiting scientist and was promoted to section head in 1979. She became a member of the distinguished Senior Executive Service in 1989 and Senior Biomedical Research Service in 1998. Dr. Dufau has won numerous awards, including the Serono Award, NIH Director’s Award, HHS Distinguished Service Award, Medal of Excellence in Research from the University of Rome, Tor Vergata, Roots Award for Contributions to the Science and Technology of Argentina, and Award for Excellence in Research from the International Congress of Oncology and Molecular Medicine, Crete, Greece. She is the recipient of the 2023 NICHD Lifetime Achievement Award for her scientific contributions during her tenure. Dr. Dufau is a member of prestigious medical societies, including the American Society for Clinical Investigation, the Association of American Physicians, and the American Endocrine Society. She also participated in the editorial boards of the Journal of Biological Chemistry, Trends in Endocrinology and Metabolism, Molecular Endocrinology, International Journal of Endocrinology, and Nature Science Reports. 

Dr. Dufau has a sustained trajectory of seminal findings and was a pioneer in the identification and characterization of cell surface LH receptor in the testis and ovary, the regulation of its transcription and expression, and its role in the hormonal control of gonadal function. She developed the first radioligand-receptor assay for LH/hCG in the testis and ovary and established their membrane localization as a separate entity from adenylate cyclase. She demonstrated the existence of LH spare receptors at the cell membrane, which maximize the efficacy of small levels of circulating hormones, and characterized the occupancy of PKCα (the regulatory subunit) at various levels of hormonal activation. Dr. Dufau established the first in vitro bioassay for LH/hCG (Rat Leydig cell testosterone bioassay-RICT) with comparable sensitivity to RIA, which permitted measurement of biological LH in human blood and of hCG from the time of implantation. She provided the first evidence of steroidogenic desensitization by LH independent of receptor down-regulation. Her laboratory characterized the genomic structure of the LHR and identified epigenetic and signal transduction mechanisms and the participation activators, re- and co-repressors involved in the transcriptional control of LHR expression. The approaches used in the laboratory facilitated the identification of several layers of regulatory modalities participating in the repression/de-repression of transcription of the LHR. Deviations in these mechanisms provide insights into unexplained disease states related to LHR expression.

Dr. Dufau’s laboratory discovered and functionally characterized a gonadotropin-regulated testicular RNA helicase (GRTH/Ddx25), solely expressed in the testis. It is the only helicase regulated by LH/androgen hormones. GRTH is a multifunctional protein, a member of the DEAD- box family of RNA helicases, and post-transcriptional regulator of genes that are essential for round spermatid elongation and completion of spermatogenesis. Males lacking GRTH are sterile due to failure of round spermatid to elongate. Her group demonstrated GRTH participation in the nuclear export/transport of specific mRNAs and transit/association to the chromatoid body of round spermatids and polyribosomes. Transgenic-mice models permitted Dr. Dufau’s group to differentially elucidate in vivo regions in the GRTH gene that directs its expression, upstream in germ cells and downstream in Leydig cells. GRTH transcription is regulated by LH through androgen/androgen receptor (A/AR) in an autocrine fashion in Leydig cells and in a paracrine mode in germ cells via Sertoli cells and GCNF (Gonadal Cell Nuclear Factor) at a site in the GRTH gene. Her studies connect androgen action to relevant cell genes essential for the progress of spermatogenesis.

Dr. Dufau’s team also provided the first evidence for the presence of a missense mutation in the GRTH gene in patients with azoospermia associated with loss of the phosphorylated cytoplasmic species. Subsequently, the lab generated a transgenic mutant mice line carrying the human mutation, and they were sterile, lacking sperm and phospho-GRTH, with preservation of the non-phospho form of GRTH. This model provided an avenue to elucidate the function of phospho-GRTH as the principal regulator of spermatogenesis. Modelling of the phospho-site based on the DDX19 crystal structure (60% identity with GRTH) and site-directed mutagenesis elucidated the amino acids that form the GRTH/PKA interface. Studies based on the abolition of phospho-GRTH provided the basis for design of a reversible chemical inhibitor as a male contraceptive. Her studies on the function of GRTH have provided insights into the intrinsic requirements of spermiogenesis and offer new approaches to investigations of infertility and male contraception. This helicase also prevents the LC from overstimulation of the androgen pathway by promoting degradation of the StAR protein, which is required for ingress of cholesterol to the mitochondria for conversion to pregnenolone. These findings have provided insights into a novel negative molecular control mechanism of this helicase in steroid production in males.

Her group also made important contributions to the elucidation of the prolactin receptor gene structure, the multiple control on PRLR expression, and on the relevance of estradiol in promoter regulation. Her group demonstrated the existence of a 3’ exon of the human receptor (exon-11), which led to the discovery of products of alternative splicing and the identification of two novel short forms (inhibitory of the functions of the long form of the human prolactin receptor) of relevance to physiological regulation and breast cancer. Combined approaches using biochemical/biophysical and molecular modeling demonstrated that the PRLR conformation is stabilized by extracellular intramolecular S-S bonds, which is required for the inhibitory action of the short forms of the PRLR on the PRL-induced long form mediated functions. These studies have provided major insights into mechanisms in which the structure impacts homo/heterodimer formation, JAK2 association, and PRL induced-PRLR action. Also, recent studies have characterized interactions and dynamics of transcription factor association that lead to transcriptional activation of PRLR by estradiol. Estrogen from stromal and adipose tissue in post-menopausal women could exert paracrine control of PRLR expression in mammary epithelial cells, and in turn, PRL/PRLR stimulation of breast tumor growth. 
Dr. Dufau ‘s scientific contributions and her leadership in the field of reproductive endocrinology is recognized both nationally and internationally. She served on the Council of the Endocrine Society and was president and an organizing committee member of major international meetings on hormone action and testicular function. 

Her overall research program is of major relevance to the general mechanism of eukaryotic gene expression and basic and clinical aspects of reproduction, fertility, and breast cancer. During her tenure, Dr. Dufau recruited many bright young scientists who made important contributions to molecular and cellular endocrinology. Their scientific achievements and the consequent reputation of the laboratory served as an attraction, continuously drawing outstanding and scientifically creative scientists to the group. Dr. Dufau coordinated research efforts of an international group of scientists and developed major collaborations with endocrine and pathology departments at the University of Charlottesville, Virginia, and the Department of Obstetrics and Gynecology at Mass. General Hospital, Harvard Medical School, and the Department of Urology and Cancer Research in Kanasawa University Medical School, Japan.  Also, she established strong collaborations within NICHD and other Institutes at the NIH. She participated in scientific exchanges with the University of Rome, La Sapienza, and Tor Vergata. Her former fellows and students have risen to prominent positions in universities, research centers, and in industry throughout the world. Dr. Dufau’s laboratory always had an extraordinary vitality, offering excellent opportunities for investigators. Her work has been published in more than 350 highly cited papers and chapters. In summary, Dr. Dufau’s work has been at the forefront of endocrine research during her tenure at the NIH, and her original and perceptive studies in reproductive endocrinology revealed important aspects of reproductive function.

Selected Publications

LH/hCG receptor-signal transduction gene structure and regulation

  • Catt KJ, Dufau ML, Tsuruhara T. Radioligand-receptor assay of luteinizing hormone and chorionic gonadotropin. J Clin Endocrinol Metab. 1972 Jan;34(1):123-32. doi: 10.1210/jcem-34-1-123. PMID: 4621461
  • Dufau ML, Mendelson CR, Catt KJ. A highly sensitive in vitro bioassay for luteinizing hormone and chorionic gonadotropin: testosterone production by dispersed Leydig cells. J Clin Endocrinol Metab. 1974 Sep;39(3):610-3. doi: 10.1210/jcem-39-3-610. PMID: 4369719
  • Dufau ML, Podesta EJ, Catt KJ. Physical characteristics of the gonadotropin receptor-hormone complexes formed in vivo and in vitro. Proc Natl Acad Sci U S A. 1975 Apr;72(4):1272-5. doi: 10.1073/pnas.72.4.1272. PMID: 165502; PMCID: PMC432514
  • Dufau ML, Hayashi K, Sala G, Baukal A, Catt KJ. Gonadal luteinizing hormone receptors and adenylate cyclase: transfer of functional ovarian luteinizing hormone receptors to adrenal fasciculata cells. Proc Natl Acad Sci U S A. 1978 Oct;75(10):4769-73. doi: 10.1073/pnas.75.10.4769. PMID: 216999; PMCID: PMC336201
  • Cigorraga SB, Sorrell S, Bator J, Catt KJ, Dufau ML. Estrogen dependence of a gonadotropin-induced steroidogenic lesion in rat testicular Leydig cells. J Clin Invest. 1980 Mar;65(3):699-705. doi: 10.1172/JCI109716. PMID: 6243676; PMCID: PMC371412

Gonadotropin-regulated RNA Helicase (GRTH/DDX25), essential for male fertility

  • Tang PZ, Tsai-Morris CH, Dufau ML. A novel gonadotropin-regulated testicular RNA helicase. A new member of the dead-box family. J Biol Chem. 1999 Dec 31;274(53):37932-40. doi: 10.1074/jbc.274.53.37932. PMID: 10608860
  • Tsai-Morris CH, Sheng Y, Lee E, Lei KJ, Dufau ML. Gonadotropin-regulated testicular RNA helicase (GRTH/Ddx25) is essential for spermatid development and completion of spermatogenesis. Proc Natl Acad Sci U S A. 2004 Apr 27;101(17):6373-8. doi: 10.1073/pnas.0401855101. Epub 2004 Apr 19. PMID: 15096601; PMCID: PMC404052
  • Kavarthapu R, Anbazhagan R, Raju M, Morris CT, Pickel J, Dufau ML. Targeted knock-in mice with a human mutation in GRTH/DDX25 reveals the essential role of phosphorylated GRTH in spermatid development during spermatogenesis. Hum Mol Genet. 2019 Aug 1;28(15):2561-2572. doi: 10.1093/hmg/ddz079. PMID: 31009948; PMCID: PMC6644162
  • Raju M, Hassan SA, Kavarthapu R, Anbazhagan R, Dufau ML. Characterization of the Phosphorylation Site of GRTH/DDX25 and Protein Kinase A Binding Interface Provides Structural Basis for the Design of a Non-Hormonal Male Contraceptive. Sci Rep. 2019 Apr 30;9(1):6705. doi: 10.1038/s41598-019-42857-9. PMID: 31040297; PMCID: PMC6491591
  • Raju M, Kavarthapu R, Anbazhagan R, Hassan SA, Dufau ML. Blockade of GRTH/DDX25 Phosphorylation by Cyclic Peptides Provides an Avenue for Developing a Nonhormonal Male Contraceptive. J Med Chem. 2021 Oct 14;64(19):14715-14727. doi: 10.1021/acs.jmedchem.1c01201. Epub 2021 Oct 2. PMID: 34601876; PMCID: PMC9446413

Prolactin receptor-structure and regulation 

  • Hu ZZ, Zhuang L, Meng J, Tsai-Morris CH, Dufau ML. Complex 5' genomic structure of the human prolactin receptor: multiple alternative exons 1 and promoter utilization. Endocrinology. 2002 Jun;143(6):2139-42. doi: 10.1210/endo.143.6.8949. PMID: 12021177
  • Qazi AM, Tsai-Morris CH, Dufau ML. Ligand-independent homo- and heterodimerization of human prolactin receptor variants: inhibitory action of the short forms by heterodimerization. Mol Endocrinol. 2006 Aug;20(8):1912-23. doi: 10.1210/me.2005-0291. Epub 2006 Mar 23. PMID: 16556730
  • Dong J, Tsai-Morris CH, Dufau ML. A novel estradiol/estrogen receptor alpha-dependent transcriptional mechanism controls expression of the human prolactin receptor. J Biol Chem. 2006 Jul 7;281(27):18825-36. doi: 10.1074/jbc.M512826200. Epub 2006 May 1. PMID: 16651265
  • Kavarthapu R, Dufau ML. Essential role of endogenous prolactin and CDK7 in estrogen-induced upregulation of the prolactin receptor in breast cancer cells. Oncotarget. 2017 Apr 18;8(16):27353-27363. doi: 10.18632/oncotarget.16040. PMID: 28423697; PMCID: PMC5432340
  • Kavarthapu R, Anbazhagan R, Dufau ML. Crosstalk between PRLR and EGFR/HER2 Signaling Pathways in Breast Cancer. Cancers (Basel). 2021 Sep 18;13(18):4685. doi: 10.3390/cancers13184685. PMID: 34572912; PMCID: PMC8467304

Access Dr. Dufau’s list of publications on the National Library of Medicine’s PubMed® database.

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