title: Transcription factor 7-like 1 is involved in hypothalamo-pituitary axis development in mice and humans.
abstract: Aberrant embryonic development of the hypothalamus and/or pituitary gland in humans results in congenital hypopituitarism (CH). Transcription factor 7-like 1 (TCF7L1), an important regulator of the WNT/β-catenin signaling pathway, is expressed in the developing forebrain and pituitary gland, but its role during hypothalamo-pituitary (HP) axis formation or involvement in human CH remains elusive. Using a conditional genetic approach in the mouse, we first demonstrate that TCF7L1 is required in the prospective hypothalamus to maintain normal expression of the hypothalamic signals involved in the induction and subsequent expansion of Rathke's pouch progenitors. Next, we reveal that the function of TCF7L1 during HP axis development depends exclusively on the repressing activity of TCF7L1 and does not require its interaction with β-catenin. Finally, we report the identification of two independent missense variants in human TCF7L1, p.R92P and p.R400Q, in a cohort of patients with forebrain and/or pituitary defects. We demonstrate that these variants exhibit reduced repressing activity in vitro and in vivo relative to wild-type TCF7L1. Together, our data provide support for a conserved molecular function of TCF7L1 as a transcriptional repressor during HP axis development in mammals and identify variants in this transcription factor that are likely to contribute to the etiology of CH.
authors.affiliation: Birth Defects Research Centre, Developmental Biology and Cancer Programme, University College London Institute of Child Health, London, WC1N 1EH, United Kingdom;
authors.forename: Carles
authors.initials: C
authors.lastname: Gaston-Massuet
authors.affiliation: Genetics and Epigenetics in Health and Disease Section, Genetics and Genomic Medicine Programme, University College London Institute of Child Health, London WC1N 1EH, United Kingdom;
authors.forename: Mark J
authors.initials: MJ
authors.lastname: McCabe
authors.affiliation: Centre for Endocrinology, William Harvey Research Institute, Barts and the London School of Medicine and Dentistry, Queen Mary University of London, London EC1M 6BQ, United Kingdom;
authors.forename: Valeria
authors.initials: V
authors.lastname: Scagliotti
authors.affiliation: Department of Cell and Developmental Biology, University College London, London WC1E 6BT, United Kingdom;
authors.forename: Rodrigo M
authors.initials: RM
authors.lastname: Young
authors.affiliation: Birth Defects Research Centre, Developmental Biology and Cancer Programme, University College London Institute of Child Health, London, WC1N 1EH, United Kingdom;
authors.forename: Gabriela
authors.initials: G
authors.lastname: Carreno
authors.affiliation: Genetics and Epigenetics in Health and Disease Section, Genetics and Genomic Medicine Programme, University College London Institute of Child Health, London WC1N 1EH, United Kingdom;
authors.forename: Louise C
authors.initials: LC
authors.lastname: Gregory
authors.affiliation: Birth Defects Research Centre, Developmental Biology and Cancer Programme, University College London Institute of Child Health, London, WC1N 1EH, United Kingdom;
authors.forename: Sujatha A
authors.initials: SA
authors.lastname: Jayakody
authors.affiliation: Birth Defects Research Centre, Developmental Biology and Cancer Programme, University College London Institute of Child Health, London, WC1N 1EH, United Kingdom;
authors.forename: Sara
authors.initials: S
authors.lastname: Pozzi
authors.affiliation: Centre for Endocrinology, William Harvey Research Institute, Barts and the London School of Medicine and Dentistry, Queen Mary University of London, London EC1M 6BQ, United Kingdom;
authors.forename: Angelica
authors.initials: A
authors.lastname: Gualtieri
authors.affiliation: Developmental and Regenerative Biology, Mount Sinai School of Medicine, New York, NY 10029;
authors.forename: Basudha
authors.initials: B
authors.lastname: Basu
authors.affiliation: Birth Defects Research Centre, Developmental Biology and Cancer Programme, University College London Institute of Child Health, London, WC1N 1EH, United Kingdom;
authors.forename: Markela
authors.initials: M
authors.lastname: Koniordou
authors.affiliation: Department of Biochemistry and Molecular Genetics, University of Illinois, Chicago, Illinois, IL 60607;
authors.forename: Chun-I
authors.initials: CI
authors.lastname: Wu
authors.affiliation: Genetics and Epigenetics in Health and Disease Section, Genetics and Genomic Medicine Programme, University College London Institute of Child Health, London WC1N 1EH, United Kingdom;
authors.forename: Rodrigo E
authors.initials: RE
authors.lastname: Bancalari
authors.affiliation: Research Unit for Pediatrics, Dermatology, Clinical Genetics, Obstetrics and Gynecology (PEDEGO) and Medical Research Center (MRC) Oulu, University of Oulu, FIN-90029, Oulu, Finland; Department of Clinical Genetics, Oulu University Hospital, FIN-90029, Oulu, Finland;
authors.forename: Elisa
authors.initials: E
authors.lastname: Rahikkala
authors.affiliation: Department of Pediatrics, PEDEGO and MRC Oulu, Oulu University Hospital, University of Oulu, FIN-90014, Oulu, Finland;
authors.forename: Riitta
authors.initials: R
authors.lastname: Veijola
authors.affiliation: Department of Child Neurology, Kuopio University Hospital, FIN 70029, Kuopio, Finland.
authors.forename: Tuija
authors.initials: T
authors.lastname: Lopponen
authors.affiliation: Centre for Endocrinology, William Harvey Research Institute, Barts and the London School of Medicine and Dentistry, Queen Mary University of London, London EC1M 6BQ, United Kingdom;
authors.forename: Federica
authors.initials: F
authors.lastname: Graziola
authors.affiliation: Genetics and Epigenetics in Health and Disease Section, Genetics and Genomic Medicine Programme, University College London Institute of Child Health, London WC1N 1EH, United Kingdom;
authors.forename: James
authors.initials: J
authors.lastname: Turton
authors.affiliation: Birth Defects Research Centre, Developmental Biology and Cancer Programme, University College London Institute of Child Health, London, WC1N 1EH, United Kingdom;
authors.forename: Massimo
authors.initials: M
authors.lastname: Signore
authors.affiliation: Birth Defects Research Centre, Developmental Biology and Cancer Programme, University College London Institute of Child Health, London, WC1N 1EH, United Kingdom;
authors.forename: Seyedeh Neda
authors.initials: SN
authors.lastname: Mousavy Gharavy
authors.affiliation: Birth Defects Research Centre, Developmental Biology and Cancer Programme, University College London Institute of Child Health, London, WC1N 1EH, United Kingdom;
authors.forename: Nicoletta
authors.initials: N
authors.lastname: Charolidi
authors.affiliation: Developmental and Regenerative Biology, Mount Sinai School of Medicine, New York, NY 10029;
authors.forename: Sergei Y
authors.initials: SY
authors.lastname: Sokol
authors.affiliation: Birth Defects Research Centre, Developmental Biology and Cancer Programme, University College London Institute of Child Health, London, WC1N 1EH, United Kingdom;
authors.forename: Cynthia Lilian
authors.identifier: http://orcid.org/0000-0003-4311-5855
authors.initials: CL
authors.lastname: Andoniadou
authors.affiliation: Department of Cell and Developmental Biology, University College London, London WC1E 6BT, United Kingdom;
authors.forename: Stephen W
authors.identifier: http://orcid.org/0000-0002-8557-5940
authors.initials: SW
authors.lastname: Wilson
authors.affiliation: Department of Biochemistry and Molecular Genetics, University of Illinois, Chicago, Illinois, IL 60607;
authors.forename: Bradley J
authors.initials: BJ
authors.lastname: Merrill
authors.affiliation: Genetics and Epigenetics in Health and Disease Section, Genetics and Genomic Medicine Programme, University College London Institute of Child Health, London WC1N 1EH, United Kingdom;
authors.forename: Mehul T
authors.initials: MT
authors.lastname: Dattani
authors.affiliation: Birth Defects Research Centre, Developmental Biology and Cancer Programme, University College London Institute of Child Health, London, WC1N 1EH, United Kingdom; j.martinez-barbera@ucl.ac.uk.
authors.forename: Juan Pedro
authors.initials: JP
authors.lastname: Martinez-Barbera
mesh_terms: D000818:Animals; D015331:Cohort Studies; D006801:Humans; D007030:Hypothalamo-Hypophyseal System; D051379:Mice; D010902:Pituitary Gland / Q000002:abnormalities / Q000378:metabolism / Q000503:physiopathology; D016548:Prosencephalon / Q000002:abnormalities / Q000378:metabolism; D058125:Transcription Factor 7-Like 1 Protein / Q000502:physiology*
chemical_list: C544912:TCF7L1 protein, human; C544913:Tcf7l1 protein, mouse; D058125:Transcription Factor 7-Like 1 Protein
keywords: Tcf7l1; WNT pathway; hypopituitarism; pituitary; septooptic dysplasia