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L. Gan, L. Feng, R. Chow; Bhlhb5 Defines the Subtype Identidities of Retinal Amacrine and Cone Bipolar Cells . Invest. Ophthalmol. Vis. Sci. 2006;47(13):3878.
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The mammalian retina consists of six major neuronal and one glial types that are further classified into many subtypes based on their anatomical aspects and functional differences. Nevertheless, how these subtypes arise remains largely unknown at molecular level. In this study, we identify Bhlhb5, an Olig–class basic helix–loop–helix (bHLH) transcription factor, as an essential regulator of cone bipolar and GABAergic amacrine cell genesis.
Immunohistochemistry and in situ hybridization methods are used to study the expression pattern of Bhlhb5. Loss–of–function experiments by gene targeting and gain–of–function studies via retroviral infection of developing mouse and chick retinas are used to investigate the in vivo role of Bhlhb5.
We demonstrate that Bhlhb5 is mainly expressed in post–mitotic retinal cells during retinogenesis. In adult retina, Bhlhb5 expression is limited to the Vsx1+ OFF–cone bipolar and the GABAergic amacrine subtypes. Targeted deletion of Bhlhb5 results in a reduction in the Vsx1+ cone bipolar and selective amacrine subtypes in mature retina. Detailed examination of developing retinas reveals the impaired genesis of cone bipolar and amacrine cells in the absence of Bhlhb5. Over–expression of Bhlhb5 in mouse and chick retinas promotes amacrine genesis. Furthermore, we show that Bhlhb5 is co–expressed with the amacrine determining factor NeuroD during amacrine development and that NeuroD and Bhlhb5 are up–regulated in Math5–cell lineages of math5–null retinas.
Targeted deletion and overexpression studies of Bhlhb5 demonstrates the essential and sufficient role of Bhlhb5 in subtype specification of cone bipolar and amacrine cells. In contrast to the roles of Atonal– and Achaete–Scute–class bHLH factors in determining the six major neuronal types in retina, our studies demonstrate for the first time that bHLH factors also execute key roles in retina subtype specification and that Bhlhb5 and Atonal–class factors Math5 and NeuroD constitute a regulatory cascade to govern the genesis of a complex retina.
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