The proliferation and expansion of retinal stem cells require functional Pax6

Xu, Shunbin; Sunderland, Mary E.; Coles, Brenda L.K.; Kam, Angela; Holowacz, Tamara; Ashery‐Padan, Ruth; Marquardt, Till; McInnes, Roderick R.; Kooy, Derek van der

doi:10.1016/j.ydbio.2007.01.021

Cited by 52 publications

(44 citation statements)

References 56 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Alexa Fluorconjugated secondary antibodies were purchased from Invitrogen. IF was performed as described previously (112). Fluorescein and rhodamine-conjugated PNA was purchased from Vector Laboratories.…”

Section: Preparation Of Cryoprotected Sections Of Adult and Embryonicmentioning

confidence: 99%

Inactivation of the microRNA-183/96/182cluster results in syndromic retinal degeneration

Lumayag

Haldin

Corbett

et al. 2013

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

Self Cite

175

241

View full text Add to dashboard Cite

The microRNA-183/96/182 cluster is highly expressed in the retina and other sensory organs. To uncover its in vivo functions in the retina, we generated a knockout mouse model, designated "miR-183CGT/GT ," using a gene-trap embryonic stem cell clone. We provide evidence that inactivation of the cluster results in early-onset and progressive synaptic defects of the photoreceptors, leading to abnormalities of scotopic and photopic electroretinograms with decreased b-wave amplitude as the primary defect and progressive retinal degeneration. In addition, inactivation of the miR-183/96/ 182 cluster resulted in global changes in retinal gene expression, with enrichment of genes important for synaptogenesis, synaptic transmission, photoreceptor morphogenesis, and phototransduction, suggesting that the miR-183/96/182 cluster plays important roles in postnatal functional differentiation and synaptic connectivity of photoreceptors. M icroRNAs (miRNAs) are small, endogenous, noncoding, regulatory RNAs and represent a newly recognized level of gene-expression regulation (1-4). miRNAs have unique expression profiles in the developing and adult retina and are involved in normal development and functions of the retina in all species studied so far (5-12). miRNAs are dysregulated in the retina of retinal degenerative mouse models, suggesting their potential involvement in retinal degeneration (13,14). Conditional inactivation of dicer, an RNase III endonuclease required for miRNA maturation in cytosol (15), in the mouse retina resulted in alteration of retinal differentiation and optic-cup patterning, increased cell death, and disorganization of axons of retinal ganglion cells (16)(17)(18)(19), suggesting that miRNAs are important for normal development and functions of the mammalian retina. However, in vivo functions of individual miRNAs in the retina still are largely unknown.Previously, we identified a highly conserved, intergenic, sensory organ-specific, paralogous miRNA cluster, the miR-183/96/182 cluster (hereafter, miR-183/96/182), contained within an ∼4-kb genomic segment on mouse chr6qA3.3 (8, 9). In the adult retina, miR-183/96/182 is expressed specifically in all photoreceptors and in the inner nuclear layer (8, 10). Developmentally, its expression is minimal in the embryonic retina but increases dramatically after birth and peaks in the adult retina, suggesting a role for miR-183/ 96/182 in maturation and normal functioning of the adult retina (8, 9). Additionally, expression of miR-183/96/182 has a diurnal pattern, suggesting a potential role in rhythmic functions of the retina (8, 9). Recently, miR-183/96/182 also was shown to be light responsive, independent of the circadian cycle (20). Targeted deletion of miR-182 alone in mouse did not result in a discernible phenotype, suggesting functional compensation by miR-183 and miR-96 (21). Point mutations of miR-96 were reported to result in progressive, nonsyndromic hearing loss in both human (22) and mouse (23); however, there was no apparent retinal phenotype, an ob...

show abstract

Section: Preparation Of Cryoprotected Sections Of Adult and Embryonicmentioning

confidence: 99%

Inactivation of the microRNA-183/96/182cluster results in syndromic retinal degeneration

Lumayag

Haldin

Corbett

et al. 2013

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

Self Cite

175

241

View full text Add to dashboard Cite

show abstract

“…The ␣-Cre line exhibits a gap in crerecombinase activity in the dorsal-temporal quadrant of the retina (Xu et al, 2007), such that Gfp expression (from the ␣-Cre transgene) (supplemental Fig. 2 B, available at www.jneurosci.org as supplemental material) and Sufu downregulation are more prominent in the ventral compared with the dorsal retina in coronal sections from the temporal side of the eye (supplemental Fig.…”

Section: Sufu Is Required In Vivo To Antagonize Hh Signaling In Rpcsmentioning

confidence: 99%

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

Cwinn¹,

Mazerolle²,

McNeill³

et al. 2011

J. Neurosci.

View full text Add to dashboard Cite

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.

show abstract

“…In both embryonic and adult neurogenesis, Pax6 is an important regulator of neural stem cell proliferation and differentiation into neurons (12,22). Although knowledge of PAX6 functions in differentiated cell types remains very scarce, it is now clear that PAX6 is maintained in several cell types of the adult eye (lens epithelium, corneal limbus, pigmented ciliary body, iris) and is implicated in self-renewal and regeneration of ocular structures (reviewed in refs.…”

Section: Ataluren For Genetic Disorders Caused By Nonsense Mutationsmentioning

confidence: 99%

Toward postnatal reversal of ocular congenital malformations

Sahel¹

2013

J. Clin. Invest.

View full text Add to dashboard Cite

The proliferation and expansion of retinal stem cells require functional Pax6

Cited by 52 publications

References 56 publications

Inactivation of the microRNA-183/96/182cluster results in syndromic retinal degeneration

Inactivation of the microRNA-183/96/182cluster results in syndromic retinal degeneration

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

Toward postnatal reversal of ocular congenital malformations

Contact Info

Product

Resources

About