期刊
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
卷 113, 期 5, 页码 E548-E557出版社
NATL ACAD SCIENCES
DOI: 10.1073/pnas.1503346113
关键词
WNT pathway; pituitary; Tcf7l1; septooptic dysplasia; hypopituitarism
资金
- Joint Medical Research Council (MRC)/Wellcome Trust Human Developmental Biology Resource [099175]
- Wellcome Trust [086545, 084361]
- MRC [164126]
- National Institute for Health Research Biomedical Research Centre at Great Ormond Street Hospital for Children National Health Service Foundation Trust
- University College London
- Great Ormond Street Children's Hospital Charity
- Medical College of Saint Bartholomew's Hospital Trust
- Action Medical Research [2272] Funding Source: researchfish
- Children with Cancer UK [15-190] Funding Source: researchfish
- Great Ormond Street Hospital Childrens Charity [W1055] Funding Source: researchfish
- Medical Research Council [MR/M000125/1, MR/L003775/1, MR/L016729/1] Funding Source: researchfish
- Wellcome Trust [104682/Z/14/Z] Funding Source: researchfish
- MRC [MR/L003775/1, MR/L016729/1, MR/M000125/1] Funding Source: UKRI
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/beta-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 beta-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.
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