Search

SoxB1 sub-family of transcriptional regulators are expressed in progenitor (NP) cells throughout the neuroaxis and are generally downregulated during neuronal differentiation. Gain- and loss-of-function studies indicate that Sox1, Sox2 and Sox3 are key regulators of NP differentiation and that their roles in CNS development are largely redundant. Nevertheless, mutation of each SoxB1 individually results in a different array of CNS defects, raising the possibility that SoxB1 proteins have subtly different functions in NP cells. To explore the mechanism of SOXB1 functional redundancy, and to identify genes that are most sensitive to loss of the Sox3 gene, we performed genome wide expression profiling of Sox3 null NP cells. Nineteen genes with abnormal expression were identified, including the homeobox gene Dbx1. Analysis of Sox3 null embryos revealed that Dbx1 was significantly reduced in the neural tube and developing brain and that SOX3 bound directly to conserved elements associated with this gene in cultured NP cells and in vivo. These data define Dbx1 as a direct SOX3 target gene whose expression, intriguingly, is not fully rescued by other SOXB1 transcription factors, suggesting that there are inherent differences in SOXB1 protein activity.

1 oktober 2010, Contains fulltext : 89315.pdf (publisher's version ) (Closed access), POU3F4 encodes a POU-domain transcription factor required for inner ear development. Defects in POU3F4 function are associated with X-linked deafness type 3 (DFN3). Multiple deletions affecting up to ~900-kb upstream of POU3F4 are found in DFN3 patients, suggesting the presence of essential POU3F4 enhancers in this region. Recently, an inner ear enhancer was reported that is absent in most DFN3 patients with upstream deletions. However, two indications suggest that additional enhancers in the POU3F4 upstream region are required for POU3F4 function during inner ear development. First, there is at least one DFN3 deletion that does not eliminate the reported enhancer. Second, the expression pattern driven by this enhancer does not fully recapitulate Pou3f4 expression in the inner ear. Here, we screened a 1-Mb region upstream of the POU3F4 gene for additional cis-regulatory elements and searched for novel DFN3 mutations in the identified POU3F4 enhancers. We found several novel enhancers for otic vesicle expression. Some of these also drive expression in kidney, pancreas and brain, tissues that are known to express Pou3f4. In addition, we report a new and smallest deletion identified so far in a DFN3 family which eliminates 3.9 kb, comprising almost exclusively the previous reported inner ear enhancer. We suggest that multiple enhancers control the expression of Pou3f4 in the inner ear and these may contribute to the phenotype observed in DFN3 patients. In addition, the novel deletion demonstrates that the previous reported enhancer, although not sufficient, is essential for POU3F4 function during inner ear development.

01 oktober 2010, Contains fulltext : 89315.pdf (publisher's version ) (Closed access), POU3F4 encodes a POU-domain transcription factor required for inner ear development. Defects in POU3F4 function are associated with X-linked deafness type 3 (DFN3). Multiple deletions affecting up to ~900-kb upstream of POU3F4 are found in DFN3 patients, suggesting the presence of essential POU3F4 enhancers in this region. Recently, an inner ear enhancer was reported that is absent in most DFN3 patients with upstream deletions. However, two indications suggest that additional enhancers in the POU3F4 upstream region are required for POU3F4 function during inner ear development. First, there is at least one DFN3 deletion that does not eliminate the reported enhancer. Second, the expression pattern driven by this enhancer does not fully recapitulate Pou3f4 expression in the inner ear. Here, we screened a 1-Mb region upstream of the POU3F4 gene for additional cis-regulatory elements and searched for novel DFN3 mutations in the identified POU3F4 enhancers. We found several novel enhancers for otic vesicle expression. Some of these also drive expression in kidney, pancreas and brain, tissues that are known to express Pou3f4. In addition, we report a new and smallest deletion identified so far in a DFN3 family which eliminates 3.9 kb, comprising almost exclusively the previous reported inner ear enhancer. We suggest that multiple enhancers control the expression of Pou3f4 in the inner ear and these may contribute to the phenotype observed in DFN3 patients. In addition, the novel deletion demonstrates that the previous reported enhancer, although not sufficient, is essential for POU3F4 function during inner ear development.