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I dentification of a conserved cis ‐regulatory element controlling mid‐diencephalic expression of mouse Six3
Author(s) -
Lee Bumwhee,
Yoon Jiyeon,
Tri Lam Duc,
Yoon Jaeseung,
Baek Kwanghee,
Jeong Yongsu
Publication year - 2017
Publication title -
genesis
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.093
H-Index - 110
eISSN - 1526-968X
pISSN - 1526-954X
DOI - 10.1002/dvg.23017
Subject(s) - enhancer , biology , haploinsufficiency , homeobox , transcription factor , genetics , regulatory sequence , pretectal area , regulation of gene expression , gene , microbiology and biotechnology , phenotype , midbrain , neuroscience , central nervous system
Summary The sine oculis homeobox protein Six3 plays pivotal roles in the development of the brain and craniofacial structures. In humans, SIX3 haploinsufficiency results in holoprosencephaly, a defect in anterior midline formation. Although much is known about the evolutionarily conserved functions of Six3 , the regulatory mechanism responsible for the expression pattern of Six3 remains relatively unexplored. To understand how the transcription of Six3 is controlled during embryogenesis, we screened ∼300 kb of genomic DNA encompassing the Six3 locus for cis ‐acting regulatory elements capable of directing reporter gene expression to sites of Six3 transcription in transgenic mouse embryos. We identified a novel enhancer element, whose activity recapitulates endogenous Six3 expression in the ventral midbrain, pretectum, and thalamus. Cross‐species comparisons revealed that this Six3 brain enhancer is functionally conserved in other vertebrates. We also showed that normal Six3 transcription in the ventral midbrain and pretectum is dependent on Ascl1 , a basic helix‐loop‐helix proneural factor. Moreover, loss of Ascl1 resulted in downregulation of the Six3 brain enhancer activity, emphasizing its unique role in regulating Six3 expression in the developing brain.