The zinc-finger, E-box-binding homeobox-2 (Zeb2) gene encodes a SMAD-interacting 
transcription factor that has diverse roles in development and disease. 
Mutations at the hZeb2 locus cause Mowat-Wilson syndrome (MWS), a genetic 
disorder that is associated with mental retardation and other, case- and 
sex-dependent clinical features. Recent studies have detailed microRNA-mediated 
control of Zeb2, but little is known about the genomic context of this gene or 
of enhancer sequences that may direct its diverse functions. Here, we describe a 
novel transgenic rodent model in which Zeb2 regulatory sequence has been 
disrupted, resulting in a postnatal developmental phenotype that is autosomal 
dominant. The phenotype exhibits a genotype-by-sex interaction and manifests 
primarily as an acute attenuation of postnatal kidney development in males. 
Other aspects of embryonic and neonatal development, including neuronal, are 
unaffected. The transgene insertion site is associated with a 12 kb deletion, 
1.2 Mb upstream of Zeb2, within a 4.1 Mb gene desert. A conserved sequence, 
derived from the deleted region, enhanced Zeb2 promoter activity in 
transcription assays. Tissue and temporal restriction of this enhancer activity 
may involve postnatal changes in proteins that bind this sequence. A control 
human/mouse VISTA enhancer (62 kb upstream of Zeb2) also up-regulated the Zeb2 
promoter, providing evidence of a string of conserved distal enhancers. The 
phenotype arising from deletion of one copy of the extreme long-range enhancer 
indicates a critical role for this enhancer at one developmental stage. 
Haploinsufficiency of Zeb2 in this developmental context reflects inheritance of 
MWS and may underlie some sex-dependent, non-neural characteristics of this 
human inherited disorder.