Atoh1, a basic helix-loop-helix transcription factor, plays a critical role in the differentiation of several epithelial and neural cell types. We found that ␤-catenin, the key mediator of the canonical Wnt pathway, increased expression of Atoh1 in mouse neuroblastoma cells and neural progenitor cells, and baseline Atoh1 expression was decreased by siRNA directed at ␤-catenin. The up-regulation of Atoh1 was caused by an interaction of ␤-catenin with the Atoh1 enhancer that could be demonstrated by chromatin immunoprecipitation. We found that two putative Tcf-Lef sites in the 3 enhancer of the Atoh1 gene displayed an affinity for ␤-catenin and were critical for the activation of Atoh1 transcription because mutation of either site decreased expression of a reporter gene downstream of the enhancer. Tcf-Lef co-activators were found in the complex that bound to these sites in the DNA together with ␤-catenin. Inhibition of Notch signaling, which has previously been shown to induce bHLH transcription factor expression, increased ␤-catenin expression in progenitor cells of the nervous system. Because this could be a mechanism for up-regulation of Atoh1 after inhibition of Notch, we tested whether siRNA to ␤-catenin prevented the increase in Atoh1 and found that ␤-catenin expression was required for increased expression of Atoh1 after Notch inhibition.Progenitor cells in several tissues require the basic helixloop-helix (bHLH) 3 transcription factor, Atoh1, for their development into mature neurons or epithelial cells (1, 2). Upstream regulators of Atoh1 are likely to have an important role in the regulation of development in the central and peripheral nervous systems and in the intestinal epithelium, all of which rely on Atoh1 for differentiation. This finding was clear from the analysis of an Atoh1-null mouse, which lacks many of the cell types of the intestinal epithelium, and has incomplete development of cerebellar and spinal neurons and a complete lack of inner ear hair cells (1). The expression of bHLH transcription factors is partly regulated by components of the Notch pathway (3-5), but these may be only a part of the complex regulatory circuits governing the timing and amount of bHLH transcription factor expression as well as the tissue specificity of expression. The Wnt pathway plays a key role in early development of several of these tissues, including the intestinal epithelium and the inner ear (6 -11), and is thus a potential candidate for upstream signaling leading to Atoh1 expression. Indeed, disruption of Wnt signaling prevents intestinal epithelial differentiation to mature cell types and is accompanied by decreased expression of Atoh1 (8).In a search for genes that affected Atoh1 expression, a number of genes were tested for their effect on Atoh1 expression by screening of an adenoviral library that allowed us to express the genes in various cell types. One such gene was ␤-catenin, the intracellular mediator of the canonical Wnt pathway. Its overexpression in neural progenitor cell types increased acti...

PURPOSE-Pathogenic variants in GJB2 are the most common cause of autosomal recessive sensorineural hearing loss. The classification of c.101T>C/p.Met34Thr and c.109G>A/p.Val37Ile in GJB2 are controversial. Therefore, an expert consensus is required for the interpretation of these two variants. METHODS-The ClinGen Hearing Loss Expert Panel collected published data and shared unpublished information from contributing laboratories and clinics regarding the two variants. Shen et al.

In our experience, primary sinonasal mucosa melanoma is prone to spread from the site of origin. The major obstacle in improving overall survival is achieving systemic control.