Distinct Effects of Hedgehog Signaling on Neuronal Fate Specification and Cell Cycle Progression in the Embryonic Mouse Retina

Sakagami, Kiyo; Gan, Lin; Yang, Xian-Jie

doi:10.1523/jneurosci.0289-09.2009

Cited by 61 publications

(78 citation statements)

References 92 publications

(107 reference statements)

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“…Proliferation is markedly reduced at embryonic stages in Pax6 CKO retina (Marquardt et al, 2001) but not in the Sufu KO retina, which is hyperplastic. This observation also illustrates that regulation of the cell cycle can be separated from the loss of multipotency associated with Pax6 downregulation, which is consistent with previous studies demonstrating the uncoupling of cell fate and proliferation in Hh pathway mutants (Sakagami et al, 2009). Therefore, although the observed downregulation of Pax6 certainly contributes to the overall Sufu-null phenotype, Sufu likely exerts some Pax6-independent effects on proliferation.…”

Section: Discussionsupporting

confidence: 91%

Suppressor of Fused Is Required to Maintain the Multipotency of Neural Progenitor Cells in the Retina

Cwinn¹,

Mazerolle²,

McNeill³

et al. 2011

J. Neurosci.

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The morphogen sonic hedgehog (Shh) plays a crucial role in development of the CNS, including the neural retina. Suppressor of fused (Sufu) has been recently identified as a critical regulator of Hh signaling in mammals. However, the precise roles that Sufu plays in the regulation of proliferation and cell-fate decisions in neural progenitors is unknown. Here, we have addressed these questions by conditionally deleting Sufu in mouse multipotent retinal progenitor cells (RPCs). Sufu deletion in RPCs results in transient increases in Hh activity and proliferation followed by developmentally premature cell-cycle exit. Importantly, we demonstrate a novel role for Sufu in the maintenance of multipotency in RPCs. Sufu-null RPCs downregulate transcription factors required to specify or maintain RPC identity (Rax, Vsx2) and multipotency (Pax6) but continue to express the neural progenitor marker Sox2. These cells fail to express retinal lineage-specific transcription factors, such as Math5, and adopt an amacrine or horizontal cell fate at the expense of all other classes of retinal neurons. Genetic elimination of Gli2 in Sufu-null RPCs attenuates Hh pathway activity and restores multipotency in neural progenitors. These data provide novel evidence that Sufu-mediated antagonism of Hh/Gli2 signaling is required to maintain RPC multipotency and identity.

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Section: Discussionsupporting

confidence: 91%

Suppressor of Fused Is Required to Maintain the Multipotency of Neural Progenitor Cells in the Retina

Cwinn¹,

Mazerolle²,

McNeill³

et al. 2011

J. Neurosci.

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“…FACS analysis was performed as described in ref. 57 and in SI Materials and Methods. For immunofluorescent labeling, cells or tissues were fixed with 4% (wt/vol) paraformaldehyde in PBS and processed as described previously (28).…”

Section: Methodsmentioning

confidence: 99%

CNTF-mediated protection of photoreceptors requires initial activation of the cytokine receptor gp130 in Müller glial cells

Rhee¹,

Nusinowitz²,

Chao³

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

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Ciliary neurotrophic factor (CNTF) acts as a potent neuroprotective agent in multiple retinal degeneration animal models. Recently, CNTF has been evaluated in clinical trials for the inherited degenerative disease retinitis pigmentosa (RP) and for dry agerelated macular degeneration (AMD). Despite its potential as a broad-spectrum therapeutic treatment for blinding diseases, the target cells of exogenous CNTF and its mechanism of action remain poorly understood. We have shown previously that constitutive expression of CNTF prevents photoreceptor death but alters the retinal transcriptome and suppresses visual function. Here, we use a lentivirus to deliver the same secreted human CNTF used in clinical trials to a mouse model of RP. We found that low levels of CNTF halt photoreceptor death, improve photoreceptor morphology, and correct opsin mislocalization. However, we did not detect corresponding improvement of retinal function as measured by the electroretinogram. Disruption of the cytokine receptor gp130 gene in Müller glia reduces CNTF-dependent photoreceptor survival and prevents phosphorylation of STAT3 and ERK in Müller glia and the rest of the retina. Targeted deletion of gp130 in rods also demolishes neuroprotection by CNTF and prevents further activation of Müller glia. Moreover, CNTF elevates the expression of LIF and endothelin 2, thus positively promoting Müller and photoreceptor interactions. We propose that exogenous CNTF initially targets Müller glia, and subsequently induces cytokines acting through gp130 in photoreceptors to promote neuronal survival. These results elucidate a cellular mechanism for exogenous CNTF-triggered neuroprotection and provide insight into the complex cellular responses induced by CNTF in diseased retinas.C iliary neurotrophic factor (CNTF) belongs to a small subfamily of cytokines and has long been recognized as a potent neuroprotective molecule in the vertebrate retina (1). Enhancement of photoreceptor survival by CNTF has been demonstrated in multiple animal models of retinal degeneration, ranging from zebrafish to canine (2). Interestingly, CNTF is effective in rescuing retinal degeneration due to various causes, including mutations in genes expressed by photoreceptors or the retinal pigment epithelium (RPE), as well as those induced by strong light, neurotoxins, or antibodies. In addition, CNTF prolongs the survival of retinal ganglion cells (3-5) and promotes axonal growth in optic nerve crush or transection models (6-8). Furthermore, CNTF may affect the physiology and survival of RPE cells (9, 10), which are critical in normal vision and retinal degenerative diseases. Based on its significant and broad neuroprotective effects in damaged retinas, a secreted form of human CNTF delivered from an encapsulated cell device has been tested in clinical trials and approved by the Food and Drug Administration (FDA) to treat retinitis pigmentosa (RP) and geographic atrophy (GA), a subset of age-related macular degeneration (AMD) (11-14). However, despite its clinical signifi...

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“…In the chick retina, Shh overexpression decreases RGC production whereas inhibiting endogenous Shh activity increases RGC differentiation (Zhang and Yang, 2001). Similarly, conditional ablation of Shh and Smoothened (Smo) in mice results in Atoh7-dependent overproduction of RGCs (Sakagami et al, 2009). VEGF (vascular endothelial growth factor) is also secreted by RGCs and other postmitotic neurons and can negatively regulate RGC differentiation (Hashimoto et al, 2006).…”

Section: Extrinsic Signalingmentioning

confidence: 99%

“…Constitutively activated Notch and elevated Dll signal are shown to decrease RGC generation whereas inhibiting Notch signaling has the opposite effect (Ahmad et al, 1997;Austin et al, 1995;Dorsky et al, 1997;Dorsky et al, 1995;Nelson et al, 2007). Interestingly, both Shh and VEGF signaling activates expression of the DllNotch effector gene Hes1, which has an activity to suppress RGC differentiation (Hashimoto et al, 2006;Sakagami et al, 2009;Wang et al, 2005). Therefore, these divergent signaling pathways appear to converge on Hes1 to control proper RGC production during retinogenesis (Hashimoto et al, 2006).…”

Section: Extrinsic Signalingmentioning

confidence: 99%

Molecular Control of Retinal Ganglion Cell Specification and Differentiation

Xiang¹,

Jiang²,

Jin³

et al. 2011

Glaucoma - Basic and Clinical Concepts

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Distinct Effects of Hedgehog Signaling on Neuronal Fate Specification and Cell Cycle Progression in the Embryonic Mouse Retina

Cited by 61 publications

References 92 publications

Suppressor of Fused Is Required to Maintain the Multipotency of Neural Progenitor Cells in the Retina

Suppressor of Fused Is Required to Maintain the Multipotency of Neural Progenitor Cells in the Retina

CNTF-mediated protection of photoreceptors requires initial activation of the cytokine receptor gp130 in Müller glial cells

Molecular Control of Retinal Ganglion Cell Specification and Differentiation

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