Dosage-dependent rescue of definitive nephrogenesis by a distant Gata3 enhancer.
Human GATA3 haploinsufficiency leads to HDR (hypoparathyroidism, deafness and renal dysplasia) syndrome, demonstrating that the development of a specific subset of organs in which this transcription factor is expressed is exquisitely sensitive to gene dosage. We previously showed that murine GATA-3 is essential for definitive kidney development, and that a large YAC transgene faithfully recapitulated GATA-3 expression in the urogenital system. Here we describe the localization and activity of a kidney enhancer (KE) located 113 kbp 5' to the Gata3 structural gene. When the KE was employed to direct renal system-specific GATA-3 transcription, the extent of cell autonomous kidney rescue in Gata3-deficient mice correlated with graded allelic expression of transgenic GATA-3. These data demonstrate that a single distant, tissue-specific enhancer can direct GATA-3 gene expression to confer all embryonic patterning information that is required for successful execution of metanephrogenesis, and that the dosage of GATA-3 required has a threshold between 50% and 70% of diploid activity.
Hasegawa
Susan L
SL
Department of Cell and Developmental Biology, University of Michigan Medical School, Ann Arbor, MI 48109-0616, USA.
Moriguchi
Takashi
T
Rao
Arvind
A
Kuroha
Takashi
T
Engel
James Douglas
JD
Lim
Kim-Chew
KC
D000818:Animals; D004622:Embryo, Mammalian / Q000196:embryology / Q000378:metabolism; D004742:Enhancer Elements, Genetic / Q000235:genetics*; D005260:Female; D050990:GATA3 Transcription Factor / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D018507:Gene Expression Regulation, Developmental / Q000235:genetics; D005838:Genotype; D007668:Kidney / Q000196:embryology* / Q000378:metabolism*; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D009154:Mutation / Q000235:genetics; D010641:Phenotype; D019076:Transgenes / Q000235:genetics
D050990:GATA3 Transcription Factor; C494748:Gata3 protein, mouse