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A mouse model for hereditary thyroid dysgenesis and cleft palate

Nature Genetics volume 19, pages 395–398 (1998)Cite this article

Abstract

Alteration of thyroid gland morphogenesis (thyroid dysgenesis) is a frequent human malformation. Among the one in three to four thousand newborns in which congenital hypothyroidism is detected, 80% have either an ectopic, small and sublingual thyroid, or have no thyroid tissue1. Most of these cases appear sporadically, although a few cases of recurring familial thyroid dysgenesis have been described2. The lack of evidence for hereditary thyroid dysgenesis may be due to the severity of the hypothyroid phenotype. Neonatal screening and early thyroid hormone therapy have eliminated most of the clinical consequences of hypothyroidism such that the heritability of this condition may become apparent in the near future. We have recently cloned cDNA encoding a forkhead domain-containing transcription factor, TTF-2, and have located the position of the gene, designated Titf2, to mouse chromosome 4 (ref. 3). Titf2 is expressed in the developing thyroid, in most of the foregut endoderm and in craniopharyngeal ectoderm, including Rathke's pouch3. Expression of Titf2 in thyroid cell precursors is down-regulated as they cease migration, suggesting that this factor is involved in the process of thyroid gland morphogenesis. Here we show that Titf2-null mutant mice exhibit cleft palate and either a sublingual or completely absent thyroid gland. Thus, mutation of Titf2 –/– results in neonatal hypothyroidism that shows similarity to thyroid dysgenesis in humans.

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Figure 1: Targeting strategy and newborn phenotype.
Figure 2: Thyroid bud at E9.5 in Titf2+/– and Titf2–/– embryos.
Figure 3: Thyroid bud at E11.5 in Titf2+/– and Titf2–/– embryos.
Figure 4: Thyroid at E15.5 in Titf2+/– and Titf2 –/– embryos.

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Acknowledgements

This work was supported by grants from TELETHON (programs n. E 406 and D 67) and by the Associazione Italiana per la Ricerca sul Cancro. A.R.M. was supported by a fellowship from UNIDO. M.D.F and A.R.M. were supported in part by short-term EMBO fellowships for the work carried out at the EMBL. We thank M. I. Arnone, H. Krude, C. Missero, A. Simeone and M. Zannini for critical reading of the manuscript.

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Author notes

  1. Angela Mariano and Vincenzo Macchia: Dipartimento di Biologia e Patologia Cellulare e Molecolare,Università Federico II, Napoli, Italy M.D. & C.O contributed equally to this work.

Authors and Affiliations

  1. Stazione Zoologica Anton Dohrn, Napoli, Italy

    Mario De Felice, Elio Biffali, Alina Rodriguez-Mallon, Paolo Emidio Macchia & Roberto Di Lauro

  2. European Molecular Biology Laboratory, Heidelberg, Germany

    Catherine Ovitt, Konstantinos Anastassiadis & Hans Schöler

  3. Istituto Nazionale dei Tumori Fondazione Senatore Pascale, Naples, Italy

    Claudio Arra

  4. Faculté de Medicine de la Timone, Marseille, France

    Marie-Genevieve Mattei

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  1. Mario De Felice
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  9. Angela Mariano
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  11. Vincenzo Macchia
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Correspondence to Roberto Di Lauro.

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De Felice, M., Ovitt, C., Biffali, E. et al. A mouse model for hereditary thyroid dysgenesis and cleft palate. Nat Genet 19, 395–398 (1998). https://doi.org/10.1038/1289

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