Requirement of FAT and DCHS protocadherins during hypothalamic-pituitary development

Emily J. Lodge, Paraskevi Xekouki, Tatiane S. Silva, Cristiane Kochi, Carlos A. Longui, Fabio R. Faucz, Alice Santambrogio, James L. Mills, Nathan Pankratz, John Lane, Dominika Sosnowska, Tina Hodgson, Amanda L. Patist, Philippa Francis-West, Françoise Helmbacher, Constantine A. Stratakis, Cynthia L. Andoniadou

Research output: Contribution to journalArticlepeer-review

1 Scopus citations

Abstract

Pituitary developmental defects lead to partial or complete hormone deficiency and significant health problems. The majority of cases are sporadic and of unknown cause. We screened 28 patients with pituitary stalk interruption syndrome for mutations in the FAT/DCHS family of protocadherins that have high functional redundancy. We identified 7 variants, 4 of which are putatively damaging, in FAT2 and DCHS2 in 6 patients with pituitary developmental defects recruited through a cohort of patients with mostly ectopic posterior pituitary gland and/or pituitary stalk interruption. All patients had growth hormone deficiency, and 2 presented with multiple hormone deficiencies and small glands. FAT2 and DCHS2 were strongly expressed in the mesenchyme surrounding the normal developing human pituitary. We analyzed Dchs2–/– mouse mutants and identified anterior pituitary hypoplasia and partially penetrant infundibular defects. Overlapping infundibular abnormalities and distinct anterior pituitary morphogenesis defects were observed in Fat4–/– and Dchs1–/– mouse mutants, but all animal models displayed normal commitment to anterior pituitary cell types. Together our data implicate FAT/DCHS protocadherins in normal hypothalamic-pituitary development and identify FAT2 and DCHS2 as candidates underlying pituitary gland developmental defects such as ectopic pituitary gland and/or pituitary stalk interruption.

Original languageEnglish (US)
Article numbere134310
JournalJCI Insight
Volume5
Issue number23
DOIs
StatePublished - Dec 3 2020

Bibliographical note

Funding Information:
We thank the patients and their families for participating in the described studies. This study was supported by grants MR/L016729/1 from the Medical Research Council (to CLA), a Lister Institute Research Prize Fellowship to CLA, RG130699 from The Royal Society (to CLA), the Deutsche Forschungsgemeinschaft within the 314061271 - TRR 205 (to CLA), the AFM-T?l?thon (Association Fran?aise contre les myopathies) grant 20861 (to FH), and grant BB/M022544/1 from the Biotechnology and Biological Sciences Research Council (to PFW). This study was in part funded by the intramural research program of the Eunice Kennedy Shriver National Institute of Child Health of Human Development, NIH, Bethesda, Maryland, USA. We are grateful to Jacques Drouin and Simon Rhodes for TPIT and PIT antibodies, respectively, and the National Hormone and Peptide Program (Harbor-University of California, Los Angeles, Medical Center) for providing some of the hormone antibodies used in this study. We thank Kenneth Irvine for continued advice and sharing reagents and Helen McNeill for providing the Fat4 mouse mutant.

Funding Information:
We thank the patients and their families for participating in the described studies. This study was supported by grants MR/L016729/1 from the Medical Research Council (to CLA), a Lister Institute Research Prize Fellowship to CLA, RG130699 from The Royal Society (to CLA), the Deutsche Forschungsgemeinschaft within the 314061271 - TRR 205 (to CLA), the AFM-Téléthon (Association Française contre les myopathies) grant 20861 (to FH), and grant BB/M022544/1 from the Biotechnology and Biological Sciences Research Council (to PFW). This study was in part funded by the intramural research program of the Eunice Kennedy Shriver National Institute of Child Health of Human Development, NIH, Bethesda, Maryland, USA. We are grateful to Jacques Drouin and Simon Rhodes for TPIT and PIT antibodies, respectively, and the National Hormone and Peptide Program (Harbor-University of California, Los Angeles, Medical Center) for providing some of the hormone antibodies used in this study. We thank Kenneth Irvine for continued advice and sharing reagents and Helen McNeill for providing the Fat4 mouse mutant.

Publisher Copyright:
Copyright: © 2020, Lodge et al.

PubMed: MeSH publication types

  • Journal Article
  • Research Support, N.I.H., Intramural
  • Research Support, Non-U.S. Gov't

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