Basic helix loop helix transcription factors are crucial for inner ear neurosensory development: Atoh1 regulates the differentiation of hair cells (HCs) and Neurog1 and Neurod1 regulate specification and differentiation of neurons, respectively. Expression of Delta and Jagged ligands in HCs and Notch receptors in supporting cells (SCs) guides supporting cell differentiation. In addition, diffusible factors from hair cells and other sources consolidate topologically correct differentiation. Hearing defects in human can result in irreversible loss of HCs and SCs. Reconstitution of organ of Corti (OC) requires topologically correct organization of the two types of HCs, inner (IHC) and outer (OHC) hair cells, as well as several types of SCs. How specific cell types differentiate in the right location is unknown. Deletion of the bHLH gene Neurod1 results in the premature, aberrant expression of Atoh1. Loss of Neurod1 in conjunction with an altered expression of Atoh1 results in the conversion of some outer hair cells (OHCs) into inner hair cells (IHCs).
In Aim1 a, I will correlate in the Neurod1 null mouse, the expression of Atoh1 using Atoh1-Cre mediated R26-YFP reporter with the expression of Delta-Notch effectors (Hes1, Hes5, Hey2) and diffusible molecules (Fgf8, Fgf10, Fgf20, BMP4).
In Aim2 a, I will analyze a novel mouse model that misexpresses Neurog1 in combination with 'self-terminating'Atoh1-Cre (Atoh1- Cre;Atoh1f/kiNeurog1).
In Aim2 b, I will investigate how the absence of Neurod1 in combination with the misexpression of Neurog1 (Atoh1-Cre;Atoh1f/kiNeurog1;Neurod1-/-) will affect certain HC markers and alter Delta-Notch patterning in the OC. These mutants will critically test the presumed causalities of molecular mechanism that regulate the patterning of the OC, including HCs and SCs differentiation, beyond correlative evidence that cannot distinguish between topology and cell specific effects.
A widespread disability in humans is hearing defects caused by progressive loss of hair cells. My proposed research will focus on the molecular mechanisms of topologically correct hair cell type development in the organ of Corti using different genetic combinations. This research will contribute to the understanding of hair cell regeneration for the attempts of organ of Corti reconstruction in patients with hearing loss.
|Jahan, Israt; Pan, Ning; Kersigo, Jennifer et al. (2015) Neurog1 can partially substitute for Atoh1 function in hair cell differentiation and maintenance during organ of Corti development. Development 142:2810-21|
|Jahan, Israt; Pan, Ning; Elliott, Karen L et al. (2015) The quest for restoring hearing: Understanding ear development more completely. Bioessays 37:1016-27|
|Fritzsch, Bernd; Pan, Ning; Jahan, Israt et al. (2015) Inner ear development: building a spiral ganglion and an organ of Corti out of unspecified ectoderm. Cell Tissue Res 361:7-24|
|Fritzsch, Bernd; Jahan, Israt; Pan, Ning et al. (2015) Evolving gene regulatory networks into cellular networks guiding adaptive behavior: an outline how single cells could have evolved into a centralized neurosensory system. Cell Tissue Res 359:295-313|
|Jahan, Israt; Pan, Ning; Fritzsch, Bernd (2015) Opportunities and limits of the one gene approach: the ability of Atoh1 to differentiate and maintain hair cells depends on the molecular context. Front Cell Neurosci 9:26|