Vsx2/Chx10 ensures the correct timing and magnitude of Hedgehog signaling in the mouse retina

Sigulinsky, Crystal; Green, Eric S.; Clark, Andrew E.; Levine, Edward M.

doi:10.1016/j.ydbio.2008.02.055

Cited by 39 publications

(47 citation statements)

References 61 publications

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“…References: the role of Hh in early embryogenesis prior to TS 15 (Chiang et al 1996;Astorga and Carlsson 2007); limb development (Ahn and Joyner 2004); cranial neural crest (Jeong et al 2004); cardiac septation (Goddeeris et al 2008); gastrointestinal system (Madison et al 2005); bladder (Haraguchi et al 2007); lung (White et al 2007); prostate ; pancreas (Hebrok et al 2000); testis development ; retina (Sigulinsky et al 2008); kidney (Hu et al 2006);hair (St-Jacques et al 1998;Jeong et al 2004); taste buds (Miura et al 2001); ear (Riccomagno et al 2002); ovary (Wijgerde et al 2005;Pangas 2007); tooth (Cobourne et al 2001(Cobourne et al , 2004; bone growth ; cerebellum growth (Hatton et al 2006;Sillitoe and Joyner 2007). site, at −1 Mb in intron 5 of the Lmbr1 gene (Sharpe et al 1999;Lettice et al 2003;Sagai et al 2004). This element is the only enhancer in Shh that has been analyzed also by loss-of-function studies (Sagai et al 2005), which conclusively demonstrate that MFCS1 is necessary for Shh expression in mouse ZPA.…”

Section: Regulatory Elements Affecting Mammalian Hh Expressionmentioning

confidence: 99%

Hedgehog: functions and mechanisms

Varjosalo¹,

Taipale²

2008

Genes Dev.

1,110

1,032

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The Hedgehog (Hh) family of proteins control cell growth, survival, and fate, and pattern almost every aspect of the vertebrate body plan. The use of a single morphogen for such a wide variety of functions is possible because cellular responses to Hh depend on the type of responding cell, the dose of Hh received, and the time cells are exposed to Hh. The Hh gradient is shaped by several proteins that are specifically required for Hh processing, secretion, and transport through tissues. The mechanism of cellular response, in turn, incorporates multiple feedback loops that fine-tune the level of signal sensed by the responding cells. Germline mutations that subtly affect Hh pathway activity are associated with developmental disorders, whereas somatic mutations activating the pathway have been linked to multiple forms of human cancer. This review focuses broadly on our current understanding of Hh signaling, from mechanisms of action to cellular and developmental functions. In addition, we review the role of Hh in the pathogenesis of human disease and the possibilities for therapeutic intervention.

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Section: Regulatory Elements Affecting Mammalian Hh Expressionmentioning

confidence: 99%

Hedgehog: functions and mechanisms

Varjosalo¹,

Taipale²

2008

Genes Dev.

1,110

1,032

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“…Vsx2 is known to be required for the proliferation of RPCs and for regulating the temporal onset of Hedgehog pathway activity (Burmeister et al, 1996;Green et al, 2003;Sigulinsky et al, 2008). The reduction in Vsx2 expression seen in both Lhx2 and Ldb1/Ldb2 retinal mutants occurred soon after the onset of Cre activity, suggesting that at least some of the activities of Ldb1/Ldb2 and Lhx2 in regulation of cell proliferation could be mediated by Vsx2.…”

Section: Ldb1 and Ldb2 Are Obligatory Co-factors Of Lhx2 In Retinal Pmentioning

confidence: 99%

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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“…This process was accompanied by RPC incompetence to re-enter S phase and by downregulation of cyclin D1. Although cyclin D1 is normally expressed by cycling RPCs, promoting progression through the cell cycle, its expression is rapidly downregulated in emerging postmitotic cells (Barton and Levine, 2008;Das et al, 2009;Dyer and Cepko, 2001). By contrast, the expression of p57…”

Section: The Role Of Pax6 In Proliferation Of Early Retinal Progenitorsmentioning

confidence: 99%

“…The expression of these bHLH factors was not initiated at E14.5 (Fig. 4H′-L′), suggesting that not only proliferation but also the retina-specific differentiation program was severely affected in the absence of Pax6.To test whether general neuronal differentiation took place in the mutants, retinae were stained with antibody against the pan-neuronal marker acetylated beta III tubulin (Tuj1, also known as Tubb3), which marks differentiating cells and reveals formation of the differentiated cell layer (DCL) (Sharma and Netland, 2007;Sigulinsky et al, 2008). Although strong Tuj1 staining was observed in the DCL of wild-type retinae at E14.5 and E16.5 (Fig.…”

mentioning

confidence: 99%

Stage-dependent requirement of neuroretinal Pax6 for lens and retina development

Klimova

Kozmík

2014

Development

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The physical contact of optic vesicle with head surface ectoderm is an initial event triggering eye morphogenesis. This interaction leads to lens specification followed by coordinated invagination of the lens placode and optic vesicle, resulting in formation of the lens, retina and retinal pigmented epithelium. Although the role of Pax6 in early lens development has been well documented, its role in optic vesicle neuroepithelium and early retinal progenitors is poorly understood. Here we show that conditional inactivation of Pax6 at distinct time points of mouse neuroretina development has a different impact on early eye morphogenesis. When Pax6 is eliminated in the retina at E10.5 using an mRx-Cre transgene, after a sufficient contact between the optic vesicle and surface ectoderm has occurred, the lens develops normally but the pool of retinal progenitor cells gradually fails to expand. Furthermore, a normal differentiation program is not initiated, leading to almost complete disappearance of the retina after birth. By contrast, when Pax6 was inactivated at the onset of contact between the optic vesicle and surface ectoderm in Pax6Sey/flox embryos, expression of lens-specific genes was not initiated and neither the lens nor the retina formed. Our data show that Pax6 in the optic vesicle is important not only for proper retina development, but also for lens formation in a non-cell-autonomous manner. KEY WORDS: Pax6, Retinal progenitor, mRx-Cre, Lens induction INTRODUCTIONProper eye development is dependent on the coordinated formation of two main tissues in the eye: the retina and the lens. Vertebrate eye development begins with invagination of the optic vesicle (OV) toward the lens-competent head surface ectoderm (SE). As OV contacts SE, a series of reciprocal inductive signals elicit formation of the lens placode (LP) and subsequent invagination of both LP and OV to form a two-layered optic cup (OC), with retinal pigmented epithelium (RPE) surrounding the retina (reviewed by Fuhrmann, 2010; Chow and Lang, 2001;Ogino et al., 2012). Genetic studies have identified multiple transcription factors and signaling pathways interacting in a complex network orchestrating early eye development (reviewed by Fuhrmann, 2010; Chow and Lang, 2001;Ogino et al., 2012;Xie and Cvekl, 2011). Among the signaling pathways, BMP (Furuta and Hogan, 1998;Rajagopal et al., 2009;Sjödal et al., 2007;Wawersik et al., 1999) and FGF (Faber et al., 2001;Garcia et al., 2011;Gotoh et al., 2004;Pan et al., 2006) were found to be essential for lens induction and coordinated OV-to-OC transition, as severe eye defects are associated with their inactivation. RESEARCH ARTICLEInstitute of Molecular Genetics, Academy of Sciences of the Czech Republic, Videnska 1083, 14420 Prague 4, Czech Republic. At the time the LP is formed, the dorsal region of the OV becomes specified to the retina and is populated with mitotically active retinal progenitor cells (RPCs) (Fuhrmann, 2010;Levine and Green, 2004). Lineage-tracing studies have shown that RPCs a...

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Vsx2/Chx10 ensures the correct timing and magnitude of Hedgehog signaling in the mouse retina

Cited by 39 publications

References 61 publications

Hedgehog: functions and mechanisms

Hedgehog: functions and mechanisms

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

Stage-dependent requirement of neuroretinal Pax6 for lens and retina development

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