Abstract
Ap-2 transcription factors comprise a family of 5 closely related sequence-specific DNA binding proteins that play pivotal and non-redundant roles in embryonic organogenesis. To investigate the function of Ap-2δ, wδe analyzed its expression during embryogenesis and generated Ap-2δ-deficient mice. In line with the specific expression pattern of Ap-2δ in the mesencephalic tectum and the dorsal midbrain, Ap-2δ-deficient mice failed to maintain the colliculus inferior, a derivative of the dorsal midbrain, as a consequence of increased apoptotic cell death. To identify specific Ap-2δ target genes in cells of the developing dorsal midbrain, we performed whole genome analysis of cDNA expression levels. This approach identified a set of 12 putative target genes being expressed in the developing midbrain, including the transcription factors Pitx2, Mef2c, Bhlhb4 and Pou4f3. Using chromatin immunoprecipitation (CHIP) we showed that some of these genes are direct targets of Ap-2δ. Consistently, we demonstrate that Ap-2δ occupies and activates the Pou4f3 and Bhlhb4 promoters. In addition, known Pou4f3 target genes were downregulated in the posterior midbrain of Ap-2δ-deficient mice. Despite the absence of a central part of the auditory pathway, the presence of neuronal responses to sounds in the neocortex of Ap-2δ-deficient mice indicates that auditory information from the brainstem still reaches the neocortex. In summary, our data define Ap-2δ as an important transcription factor, specifying gene expression patterns required for the development of the posterior midbrain.
Highlights
Ap-2 transcription factors are closely related, sequence-specific DNA-binding proteins that play pivotal roles in regulating gene expression during development, differentiation, and tumorigenesis [1]
Ap-2d, shows a highly dynamic expression pattern, in which it becomes enriched in the posterior midbrain and declines in the anterior midbrain
A similar expression pattern has not been described for any other Ap-2 transcription factor
Summary
Ap-2 transcription factors are closely related, sequence-specific DNA-binding proteins that play pivotal roles in regulating gene expression during development, differentiation, and tumorigenesis [1]. Ap-2a, Ap-2b and Ap-2c show partially overlapping expression patterns in neural crest cells, the central and peripheral nervous system, the facial mesenchyme, the limbs, various epithelia of the developing embryo, and the extraembryonic trophectoderm [2,3,4]. The more recently characterized Ap-2 transcription factors, Ap-2d and Ap-2e, show a more restricted expression pattern and are almost exclusively expressed in the central nervous system. Ap-2d is expressed at lower levels in the diencephalon, forebrain, spinal cord and the retina and for a short period in the developing heart [8]
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