Abstract
BackgroundWNT4 is a critical signalling molecule in embryogenesis and homeostasis, but the elements that control its transcriptional regulation are largely unknown. This study uses comparative cross species sequence and functional analyses between humans and a marsupial (the tammar wallaby,Macropus eugenii) to refine the mammalian Wnt4 promoter.ResultsWe have defined a highly conserved 89 bp minimal promoter region in human WNT4 by comparative analysis with the tammar wallaby. There are many conserved transcription factor binding sites in the proximal promoter region, including SP1, MyoD, NFκB and AP2, as well as highly conserved CpG islands within the human, mouse and marsupial promoters, suggesting that DNA methylation may play an important role in WNT4 transcriptional regulation.ConclusionUsing a marsupial model, we have been able to provide new information on the transcriptional regulators in the promoter of this essential mammalian developmental gene, WNT4. These transcription factor binding sites and CpG islands are highly conserved in two disparate mammals, and are likely key controlling elements in the regulation of this essential developmental gene.
Highlights
WNT4 is a critical signalling molecule in embryogenesis and homeostasis, but the elements that control its transcriptional regulation are largely unknown
Cloning of tammar and human WNT4 5' flanking sequence Since there were no EcoRI restriction enzyme sites identified in the tammar wallaby WNT4 cDNA sequence, this enzyme was used to create a shotgun library of a WNT4 containing tammar BAC clone (166C18 from Macropus eugenii BAC library; ME_KBa, Arizona Genomics Institute, USA) [13] in pBluescript II SK (-) vector
The transcription start site was determined according to our previous analysis of the tammar WNT4 gene [13] and all of transcripts/isoforms were obtained with the same untranslated region
Summary
WNT4 is a critical signalling molecule in embryogenesis and homeostasis, but the elements that control its transcriptional regulation are largely unknown. Wingless-type MMTV integration site family, member 4 (WNT4) is a locally acting signalling molecule, regulating cell-cell interactions, proliferation, differentiation, migration, and gene activation [1,2,3,4,5,6,7,8,9,10] It is a highly conserved gene within mammals and has multiple roles in organogenesis and homeostasis and is of special interest in the sexual differentiation of the ovary [11,12,13,14,15,16,17,18,19,20,21,22,23,24]. We know that WNT4 appears to be as important in differentiation of the marsupial ovary as it is in eutherians [13], suggesting that this gene has been highly conserved during therian
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