Dosage-dependent rescue of definitive nephrogenesis by a distant Gata3 enhancer

作者：Hasegawa Susan L; Moriguchi Takashi; Rao Arvind; Kuroha Takashi; Engel James Douglas^*; Lim Kim Chew

来源：Developmental Biology, 2007, 301(2): 568-577.

DOI：10.1016/j.ydbio.2006.09.030

• Gata3
• kidney
• rescue
• enhancer
• allelic series
• haploinsufficiency

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 transgenie 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.

• 出版日期2007-1-15
• 单位西北大学