Nature Genetics
19, 395 - 398 (1998)
doi:10.1038/1289
A mouse model for hereditary thyroid dysgenesis and cleft palateMario De Felice1, Catherine Ovitt2, Elio Biffali1, Alina Rodriguez-Mallon1, Claudio Arra3, Konstantinos Anastassiadis2, Paolo Emidio Macchia1, Marie-Genevieve Mattei4, Angela Mariano5, Hans Schöler2, Vincenzo Macchia5
& Roberto Di Lauro11
Stazione Zoologica Anton Dohrn, Napoli, Italy. 2
European Molecular Biology Laboratory, Heidelberg, Germany. 3
Istituto Nazionale dei Tumori Fondazione Senatore Pascale, Naples, Italy. 4
Faculté de Medicine de la Timone, Marseille, France. 5
Dipartimento di Biologia e Patologia Cellulare e Molecolare,Università Federico II, Napoli, Italy M.D. & C.O contributed equally to this work.
Correspondence should be addressed to Roberto Di Lauro rdilauro@unina.it.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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