Ldb1 and Rnf12-dependent regulation of Lhx2 controls the relative balance between neurogenesis and gliogenesis in retina

Abstract

Precise control of the relative ratio of retinal neurons and glia generated during development is essential for visual function. We show that <i>Lhx2</i>, which encodes a LIM-homeodomain transcription factor essential for specification and differentiation of retinal Müller glia, also plays a crucial role in the development of retinal neurons. Overexpression of <i>Lhx2</i> with its transcriptional co-activator <i>Ldb1</i> triggers cell cycle exit and inhibits both Notch signaling and retinal gliogenesis. <i>Lhx2</i>/<i>Ldb1</i> overexpression also induces the formation of wide-field amacrine cells (wfACs). In contrast, <i>Rnf12</i>, which encodes a negative regulator of LDB1, is necessary for the initiation of retinal gliogenesis. We also show that Lhx2-dependent neurogenesis and wfAC formation requires <i>Ascl1</i> and <i>Neurog2</i>, and that Lhx2 is necessary for their expression, although overexpression of <i>Lhx2</i>/<i>Ldb1</i> does not elevate expression of these proneural bHLH factors. Finally, we demonstrate that the relative level of the LHX2-LDB1 complex in the retina decreases in tandem with the onset of gliogenesis. These findings show that control of <i>Lhx2</i> function by <i>Ldb1</i> and <i>Rnf12</i> underpins the coordinated differentiation of neurons and Müller glia in postnatal retina.