Retinoic Acid Signaling Mediates Hair Cell Regeneration by Repressing p27kip and sox2 in Supporting Cells.

Unlabelled: During development, otic sensory progenitors give rise to hair cells and supporting cells. In mammalian adults, differentiated and quiescent sensory cells are unable to generate new hair cells when these are lost due to various insults, leading to irreversible hearing loss. Retinoic acid (RA) has strong regenerative capacity in several organs, but its role in hair cell regeneration is unknown.

Characterization of new otic enhancers of the pou3f4 gene reveal distinct signaling pathway regulation and spatio-temporal patterns.

POU3F4 is a member of the POU-homedomain transcription factor family with a prominent role in inner ear development. Mutations in the human POU3F4 coding unit leads to X-linked deafness type 3 (DFN3), characterized by conductive hearing loss and progressive sensorineural deafness. Microdeletions found 1 Mb 5' upstream of the coding region also displayed the same phenotype, suggesting that cis-regulatory elements might be present in that region.

Her9 represses neurogenic fate downstream of Tbx1 and retinoic acid signaling in the inner ear.

Proper spatial control of neurogenesis in the inner ear ensures the precise innervation of mechanotransducing cells and the propagation of auditory and equilibrium stimuli to the brain. Members of the Hairy and enhancer of split (Hes) gene family regulate neurogenesis by inhibiting neuronal differentiation and maintaining neural stem cell pools in non-neurogenic zones. Remarkably, their role in the spatial control of neurogenesis in the ear is unknown.

The Notch pathway in the developing hematopoietic system.

The main function of the Notch signaling pathway is to generate cell diversity during both embryonic development and adult tissue homeostasis. The extended use of this pathway, together with its conservation during evolution, is indicative of its importance. During embryonic development, the vascular and hematopoietic systems are intimately associated and Notch signals are responsible for the correct specification of both systems.

Multiple enhancers located in a 1-Mb region upstream of POU3F4 promote expression during inner ear development and may be required for hearing.

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.

Jagged1 is the pathological link between Wnt and Notch pathways in colorectal cancer.

Notch has been linked to beta-catenin-dependent tumorigenesis; however, the mechanisms leading to Notch activation and the contribution of the Notch pathway to colorectal cancer is not yet understood. By microarray analysis, we have identified a group of genes downstream of Wnt/beta-catenin (down-regulated when blocking Wnt/beta-catenin) that are directly regulated by Notch (repressed by gamma-secretase inhibitors and up-regulated by active Notch1 in the absence of beta-catenin signaling). We demonstrate that Notch is downstream of Wnt in colorectal cancer cells through beta-catenin-mediated transcriptional activation of the Notch-ligand Jagged1.

Impaired embryonic haematopoiesis yet normal arterial development in the absence of the Notch ligand Jagged1.

Specific deletion of Notch1 and RBPjkappa in the mouse results in abrogation of definitive haematopoiesis concomitant with the loss of arterial identity at embryonic stage. As prior arterial determination is likely to be required for the generation of embryonic haematopoiesis, it is difficult to establish the specific haematopoietic role of Notch in these mutants. By analysing different Notch-ligand-null embryos, we now show that Jagged1 is not required for the establishment of the arterial fate but it is required for the correct execution of the definitive haematopoietic programme, including expression of GATA2 in the dorsal aorta.

RBPjkappa-dependent Notch function regulates Gata2 and is essential for the formation of intra-embryonic hematopoietic cells.

Definitive hematopoiesis in the mouse embryo originates from the aortic floor in the P-Sp/AGM region in close association with endothelial cells. An important role for Notch1 in the control of hematopoietic ontogeny has been recently established, although its mechanism of action is poorly understood. Here, we show detailed analysis of Notch family gene expression in the aorta endothelium between embryonic day (E) 9.

IkappaBalpha and p65 regulate the cytoplasmic shuttling of nuclear corepressors: cross-talk between Notch and NFkappaB pathways.

Notch and NFkappaB pathways are key regulators of numerous cellular events such as proliferation, differentiation, or apoptosis. In both pathways, association of effector proteins with nuclear corepressors is responsible for their negative regulation. We have previously described that expression of a p65-NFkappaB mutant that lacks the transactivation domain (p65DeltaTA) induces cytoplasmic translocation of N-CoR leading to a positive regulation of different promoters.