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 Lhx2, which encodes a LIM-homeodomain transcription factor essential for specification and differentiation of retinal Müller glia, also plays a critical role in the development of retinal neurons. Overexpression of Lhx2, and its transcriptional coactivator Ldb1, triggers cell cycle exit and inhibits both Notch signaling and retinal gliogenesis.Lhx2/Ldb1 overexpression also induced the formation of wide-field amacrine cells (wfACs). In contrast Rnf12, which encodes a negative regulator of LDB1, is necessary for the initiation of retinal gliogenesis. We also show that LHX2 protein binds upstream of multiple neurogenic bHLH factors including Ascl1 and Neurog2, which are necessary for suppression of gliogenesis and wfAC formation respectively, and activates their expression. 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 Lhx2All rights reserved. No reuse allowed without permission.was not peer-reviewed) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity.The copyright holder for this preprint (which . http://dx.doi.org/10.1101/183285 doi: bioRxiv preprint first posted online Sep. 1, 2017; 2 function by Ldb1 and Rnf12 acts as a molecular mechanism underpinning the coordinated differentiation of neurons and Müller glia in postnatal retina. Significance StatementThe molecular mechanisms that control the ratio neurons and glia that are generated by neuronal progenitors remain unclear. Here we show that Lhx2, a transcription factor essential for retinal gliogenesis, also controls development of retinal neurons. The Lhx2 coactivator Ldb1 promotes Lhx2-dependent neurogenesis, while the Lhx2 corepressor Rnf12 is necessary and sufficient for retinal gliogenesis. Furthermore, Lhx2 directly regulates expression of bHLH factors that promote neural development, which are necessary for Lhx2-dependent neurogenesis. Finally, we show that levels of the LHX2-LDB1 complex, which activates transcription, drop as gliogenesis begins. Dynamic regulation of Lhx2 activity by Ldb1 and Rnf12 thus controls the relative levels of retinal neurogenesis and gliogenesis, and may have similar functions elsewhere in the developing nervous system.

Requirements for Neurogenin2 during mouse postnatal retinal neurogenesis

“…Multiple studies have documented Neurog2 expression in retinal progenitor cells (RPCs) between E11 to P2 (Akagi et al, 2004; Brown et al, 1998; Brzezinski et al, 2011; de Melo et al, 2018; Ma et al, 1996; Skowronska-Krawczyk et al, 2009), although there is conflicting data about when this gene shuts off between postnatal day 0 (P0) and P2. So, we labeled early postnatal retinal cryosections with a validated antibody and directly compared Neurog2 expression.…”

Epigenomic profiling of retinal progenitors reveals LHX2 is required for developmental regulation of open chromatin

“…Notably, immunostaining for P27 Kip1 and GLUL in Müller Glia is reduced both by overexpression 23 and downregulation of Lhx2 in the neonatal retina 9 , suggesting a balanced amount of LHX2 protein may be necessary to mediate the gliogenic process and a graded transcriptional response of target genes. Transcriptional de-regulation of P27 Kip1 and Glul may ultimately result from threshold responses that override the feed-forward regulatory loop controlling Lhx2 expression.…”

Cooperation of LIM domain‐binding 2 (LDB2) with EGR in the pathogenesis of schizophrenia

“…Mammals have a close homolog to LDB2, namely LDB1 (Matthews & Visvader, 2003; Love et al , 2014), and many studies have reported the role of LDB1 in multiple biological processes (Love et al , 2014; Costello et al , 2015; Ediger et al , 2017; de Melo et al , 2018; Kinare et al , 2019). In contrast, little is known about the biological functions of LDB2, especially in the brain, while the protein has been regarded as a layer V‐specific expression marker in the cerebral cortex (Bulchand et al , 2003; Molyneaux et al , 2007).…”