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Figure 7. Atoh1-regulated Barhl1 expression during the organ of Corti development. Left panel: A concise outline of the cochlear development with cross sections at corresponding periods listed next to it. The cochlear duct commences with an expansion of the ventral part of the otocyst. A diagram of the entire cochlea at E11.5 highlights the expression of Sox2 (indicated by yellow) in the pro-sensory region. Several cyclin-dependent kinase inhibitors urge the pro-sensory cells to exit from cell cycles and this withdrawal originates from the apex and extends towards the base at E12.5. The gradient expression of p27 (indicated by red arrow) is consistent with the direction of cell cycle exit in the cochlea. Then the pro-sensory cells are guided into hair cell fate and supporting cell fate separately by Atoh1 and Notch signaling pathways. Atoh1 first expresses in the post mitotic pro-sensory region at E13.5, which signifies the beginning of hair cell differentiation. Then Atoh1 expands its expression from the midbase to both the apex and base of the duct bidirectionally (indicated by green arrows). Notch, Hey1,2, and Hes1,5 (indicated by pink) direct pro-sensory cells to supporting cells. For the survival and maintenance of hair cells, multiple cell signaling pathways and genes are involved. Barhl1 first appears at E14.5 in the mid-base of cochlea and its expression pattern (indicated by blue arrows) follows that of Atoh1. At P6, Atoh1 expression ceases while Barhl1 expression continues to maintain the normal function of hair cells. Right panel: Schematics showing Atoh1 drives Barhl1 expression through the E3 site in the 3′ enhancer. In the WT cell line, Atoh1 binds to the E3 site located at the 3′ enhancer to activate Barhl1 expression, thereby driving the differentiation of pro-sensory cells into nascent hair cells. When Atoh1 stops its expression at P6, Barhl1 can bind to the promoter region to maintain its own expression to form mature hair cells. However, in the BEM cell line, since Atoh1 cannot bind to the mutated E3 site in the 3′ enhancer, the expression of Barhl1 failed to be activated, leading to the failure of nascent hair cell differentiation from pro-sensory cells. Blue boxes, UTRs; yellow boxes, Barhl1 coding sequence (CDS); gray boxes, promoter and enhancer; black arrow, direction of transcription. Image published in: Hou K et al. (2019) © 2019 by the authors. This image is reproduced with permission of the journal and the copyright holder. This is an open-access article distributed under the terms of the Creative Commons Attribution license Larger Image Printer Friendly View

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