Lhx2 Is an Essential Factor for Retinal Gliogenesis and Notch Signaling

Melo, Jimmy de; Zibetti, Cristina; Clark, Brian S.; Hwang, Woochang; Miranda-Angulo, Ana L.; Qian, Jiang; Blackshaw, Seth

doi:10.1523/jneurosci.3145-15.2016

Cited by 84 publications

(121 citation statements)

References 61 publications

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“…We also noted ectopic misexpression of the hypothalamic gene Lhx5 in the Ldb1/Ldb2 mutant at E16.5, similar to ectopic expression reported for Lhx2 mutants (Fig. S3) (Roy et al, 2013;de Melo et al, 2016). The observed interaction between Lhx2 and Ldb1, along with the phenotypic similarity between the Ldb1/Ldb2-and Lhx2-deficient RPCs, supports the notion that Ldb proteins are required for Lhx2 function in RPCs.…”

Section: ;Ldb2supporting

confidence: 87%

“…Premature differentiation was previously reported to occur upon loss of Notch signaling factors (Jadhav et al, 2006a;Yaron et al, 2006), and the Notch-target gene Hes1 was recently reported to be downstream of the Ldb co-factor Lhx2 in cortical and late RPCs (Chou and O'Leary, 2013;Gordon et al, 2013;de Melo et al, 2016). Therefore, we sought to determine whether the Ldb1/Ldb2 complex regulates Notch signaling components during retinogenesis.…”

Section: ;Ldb2mentioning

confidence: 99%

“…(H) Ldb1 ChIP was performed on retinal tissue collected at P0. Scatter plot represents fold enrichment for the immunoprecipitated fractions relative to the isotype controls at regulatory sites of Vsx2 and Rax genes that were found to be bound by Lhx2 at positive sites (blue dots; de Melo et al, 2016) and at negative sites (orange diamonds). The horizontal lines indicate the mean fold enrichment of Vsx2 (n=3, *P=0.02) and Rax (n=4, *P=0.037) calculated using a one-tailed paired-t-test.…”

Section: ;Ldb2mentioning

confidence: 99%

“…Having shown a physical interaction between Ldb1 and Lhx2 in P0 retinas and a role for Ldb1/Ldb2 in maintaining the RPC progenitor pool through regulation of the expression of factors required for RPC proliferation, we further investigated [using chromatin immunoprecipitation (ChIP)-qPCR on P0 retina] whether Ldb1 directly binds candidate cis-regulatory sequences targeted by Lhx2 at this stage (de Melo et al, 2016). Ldb1 was found to be highly enriched in the regulatory regions of Vsx2, compared with IgG controls and with regions located downstream of these sites (termed 'negative sites').…”

Section: ;Ldb2mentioning

confidence: 99%

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The stage-dependent roles of Ldb1 and functional redundancy with Ldb2 in mammalian retinogenesis

et al. 2016

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The Lim domain-binding proteins are key co-factor proteins that assemble with LIM domains of the LMO/LIM-HD family to form functional complexes that regulate cell proliferation and differentiation. Using conditional mutagenesis and comparative phenotypic analysis, we analyze the function of Ldb1 and Ldb2 in mouse retinal development, and demonstrate overlapping and specific functions of both proteins. Ldb1 interacts with Lhx2 in the embryonic retina and both Ldb1 and Ldb2 play a key role in maintaining the pool of retinal progenitor cells. This is accomplished by controlling the expression of the Vsx2 and Rax, and components of the Notch and Hedgehog signaling pathways. Furthermore, the Ldb1/Ldb2-mediated complex is essential for generation of earlyborn photoreceptors through the regulation of Rax and Crx. Finally, we demonstrate functional redundancy between Ldb1 and Ldb2. Ldb1 can fully compensate the loss of Ldb2 during all phases of retinal development, whereas Ldb2 alone is sufficient to sustain activity of Lhx2 in both early-and late-stage RPCs and in Müller glia. By contrast, loss of Ldb1 disrupts activity of the LIM domain factors in neuronal precursors. An intricate regulatory network exists that is mediated by Ldb1 and Ldb2, and promotes RPC proliferation and multipotency; it also controls specification of mammalian retina cells.

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Section: ;Ldb2supporting

confidence: 87%

Section: ;Ldb2mentioning

confidence: 99%

Section: ;Ldb2mentioning

confidence: 99%

Section: ;Ldb2mentioning

confidence: 99%

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The stage-dependent roles of Ldb1 and functional redundancy with Ldb2 in mammalian retinogenesis

et al. 2016

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“…Our finding that Lhx2 regulates neuroretinal FGFs is supported by a previous study from our lab that showed direct binding of Lhx2 to cis-regulatory regions of Fgf15 in neonatal mouse retina (de Melo et al, 2016). Although neuroretina-specific loss of function of other retinal progenitor-expressed transcription factors disrupts retinal progenitor cell proliferation and differentiation, and leads to microphthalmia (Burmeister et al, 1996;Marquardt et al, 2001;Taranova et al, 2006), only loss of Lhx2 significantly disrupts lens development.…”

Section: Discussionsupporting

confidence: 86%

Control of lens development by Lhx2-regulated neuroretinal FGFs

et al. 2016

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Fibroblast growth factor (FGF) signaling is an essential regulator of lens epithelial cell proliferation and survival, as well as lens fiber cell differentiation. However, the identities of these FGF factors, their source tissue and the genes that regulate their synthesis are unknown. We have found that Chx10-Cre;Lhx2 lox/lox mice, which selectively lack Lhx2 expression in neuroretina from E10.5, showed an early arrest in lens fiber development along with severe microphthalmia. These mutant animals showed reduced expression of multiple neuroretina-expressed FGFs and canonical FGFregulated genes in neuroretina. When FGF expression was genetically restored in Lhx2-deficient neuroretina of Chx10-Cre; Lhx2 lox/lox mice, we observed a partial but nonetheless substantial rescue of the defects in lens cell proliferation, survival and fiber differentiation. These data demonstrate that neuroretinal expression of Lhx2 and neuroretina-derived FGF factors are crucial for lens fiber development in vivo.

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Multiomic Analysis of Neurons with Divergent Projection Patterns Identifies Novel Regulators of Axon Pathfinding

et al. 2022

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Axon pathfinding is a key step in neural circuits formation. However, the transcriptional mechanisms regulating its progression remain poorly understood. The binary decision of crossing or avoiding the midline taken by some neuronal axons during development represents a robust model to investigate the mechanisms that control the selection of axonal trajectories. Here, to identify novel regulators of axon guidance, this work compares the transcriptome and chromatin occupancy profiles of two neuronal subpopulations, ipsilateral (iRGC) and contralateral retinal ganglion cells (cRGC), with similar functions but divergent axon trajectories. These analyses retrieved a number of genes encoding for proteins not previously implicated in axon pathfinding. In vivo functional experiments confirm the implication of some of these candidates in axonal navigation. Among the candidate genes, 𝜸-synuclein is identified as essential for inducing midline crossing. Footprint and luciferase assays demonstrate that this small-sized protein is regulated by the transcription factor (TF) Pou4f1 in cRGCs. It is also shown that Lhx2/9 are specifically expressed in iRGCs and control a program that partially overlaps with that regulated by Zic2, previously described as essential for iRGC specification. Overall, the analyses identify dozens of new molecules potentially involved in axon guidance and reveal the regulatory logic behind the selection of axonal trajectories.

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Lhx2 Is an Essential Factor for Retinal Gliogenesis and Notch Signaling

Cited by 84 publications

References 61 publications

The stage-dependent roles of Ldb1 and functional redundancy with Ldb2 in mammalian retinogenesis

The stage-dependent roles of Ldb1 and functional redundancy with Ldb2 in mammalian retinogenesis

Control of lens development by Lhx2-regulated neuroretinal FGFs

Multiomic Analysis of Neurons with Divergent Projection Patterns Identifies Novel Regulators of Axon Pathfinding

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