Bone Morphogenetic Protein 4 (BMP4) is a member of the TGF-β superfamily and is known to be important for the normal development of many tissues and organs, including the inner ear. Bmp4 homozygous null mice die as embryos, but Bmp4 heterozygous null (Bmp4 +/− ) mice are viable and some adults exhibit a circling phenotype, suggestive of an inner ear defect. To understand the role of BMP4 in inner ear development and function, we have begun to study C57BL/6 Bmp4 +/− mice. Quantitative testing of the vestibulo-collic reflex, which helps maintain head stability, demonstrated that Bmp4 +/− mice that exhibit circling behavior have a poor response in the yaw axis, consistent with semicircular canal dysfunction. Although the hair cells of the ampullae were grossly normal, the stereocilia were greatly reduced in number. Auditory brainstem responses showed that Bmp4 +/− mice have elevated hearing thresholds and immunohistochemical staining demonstrated decreased numbers of neuronal processes in the organ of Corti. Thus Bmp4 +/− mice have structural and functional deficits in the inner ear.
Accumulation of histone proteins is necessary for packaging of replicated DNA during the S-phase of cell cycle. Different mechanisms operate to regulate histone protein levels and induction of human histone gene expression at the G1/S phase transition plays a critical role. The zinc finger HiNF-P and co-activator p220 NPAT proteins are key regulators of histone gene expression. Here, we describe a novel HiNF-P-specific conserved region (PSCR) located within the C-terminus that is present in HiNF-P homologs of all metazoan species examined. The PSCR motif is required for activation of histone H4 gene transcription, and contributes to DNA binding of HiNF-P. Thus, the PSCR module represents an auxiliary DNA-binding determinant that plays a critical role in mediating histone gene expression during the cell cycle and defines HiNF-P as a unique cell cycle regulatory member of the zinc finger transcription factor family.Keywords cell cycle; histone; HiNF-P; p220 NPAT ; CDK2; cyclin E; S phase; DNA-binding; zinc finger Histone protein synthesis must be finely coupled to DNA replication to accommodate the newly synthesized DNA during the S-phase of the cell cycle (1,2). Stringent control of histone gene expression is essential for normal cell proliferation and abrogation of histone gene-related cell cycle mechanisms blocks cell growth (3). Multiple levels of regulation operate to ensure that histones are synthesized solely during the period of DNA synthesis. As a consequence of this orchestrated control, accumulation of histone mRNA is observed only when the protein is required. Transcriptional and posttranscriptional mechanisms regulate the level of histone mRNA during this period of the cell cycle. At the G1/S transition phase the histone mRNA synthesis increases three to five fold (4-7). Post-transcriptional mechanisms include cell cycle regulation of the half-life of histone mRNAs (8) and S-phase specific endonucleolytic cleavage of the 3'-end of pre-mRNAs (9,10).The histone transcription factor HiNF-P is a critical component of a signaling pathway that controls expression of histone H4 genes during the S-phase (11-13). HiNF-P exerts its regulatory function by physically interacting with and controlling the stability of p220 NPAT (14,15), a nuclear protein substrate of the cyclin E/CDK2 kinase complex that localizes to specific sub-nuclear foci (16-18). The HiNF-P/p220 NPAT activation complex coordinately
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