Regulation of retinal interneuron subtype identity by the<i>Iroquois</i>homeobox gene<i>Irx6</i>

Star, Erin N.; Zhu, Minyan; Shi, Zhiwei; Liu, Haiquan; Pashmforoush, Mohammad; Sauvé, Yves; Bruneau, Benoit G.; Chow, Robert L.

doi:10.1242/dev.081729

Cited by 29 publications

(22 citation statements)

References 42 publications

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“…8). In contrast, another group of TFs is required for the differentiation but not the survival of BP subtypes, including IRX5 (2), IRX6 (32), and VSX1 (3).…”

Section: Discussionmentioning

confidence: 99%

Transcription factor PRDM8 is required for rod bipolar and type 2 OFF-cone bipolar cell survival and amacrine subtype identity

Jung

Atan

et al. 2015

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

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Retinal bipolar (BP) cells mediate the earliest steps in image processing in the visual system, but the genetic pathways that regulate their development and function are incompletely known. We identified PRDI-BF1 and RIZ homology domain containing 8 (PRDM8) as a highly conserved transcription factor that is abundantly expressed in mouse retina. During development and in maturity, PRDM8 is expressed strongly in BP cells and a fraction of amacrine and ganglion cells. To determine whether Prdm8 is essential to BP cell development or physiology, we targeted the gene in mice. Prdm8 EGFP/EGFP mice showed nonprogressive b-wave deficits on electroretinograms, consistent with compromised BP cell function or circuitry resembling the incomplete form of human congenital stationary night blindness (CSNB). BP cell specification was normal in Prdm8 EGFP/EGFP retina as determined by VSX2 + cell numbers and retinal morphology at postnatal day 6. BP subtype differentiation was impaired, however, as indicated by absent or diminished expression of BP subtype-specific markers, including the putative PRDM8 regulatory target PKCα (Prkca) and its protein. By adulthood, rod bipolar (RB) and type 2 OFF-cone bipolar (CB) cells were nearly absent from Prdm8-null mice. Although no change was detected in total amacrine cell (AC) numbers, increased PRKCA + and cholinergic ACs and decreased GABAergic ACs were seen, suggesting an alteration in amacrine subtype identity. These findings establish that PRDM8 is required for RB and type 2 OFF-CB cell survival and amacrine subtype identity, and they present PRDM8 as a candidate gene for human CSNB.retina | bipolar cell | amacrine cell | genetics | development R etinal bipolar (BP) cells are the first interneurons in the mammalian visual signaling pathway, connecting photoreceptors (PRs) to ganglion cells and then, through the optic nerve, to the brain. In mouse retina, 13 BP subtypes are distinguished by their (i) predominant presynaptic (rod or cone) input, (ii) morphology (axon length and terminal field width), (iii) functional response to increased illumination (depolarizing or ON-BP cells and hyperpolarizing or OFF-BP cells), and (iv) molecular markers (1). Mouse retina has only one type of rod BP (RB) cell, primarily postsynaptic to rod PRs, which extends its axon to the innermost sublamina of the inner plexiform layer (IPL) and depolarizes in response to increments in illumination. The axons of cone BP (CB) cells ramify throughout the IPL, but those that terminate in the outer sublaminae are functionally OFF-CB cells that hyperpolarize to light increments, whereas those that terminate in the inner sublaminae are ON-CB cells (1). Moreover, ON-and OFF-BP cells make direct and indirect synaptic connections with corresponding ON-and OFF-retinal ganglion cells (RGCs) in the IPL. The ON and OFF properties of BP cells result from differences in glutamate receptor activity on BP cell dendrites (1). Hence, the early integration of visual signals in the mammalian retina is determined by the specific syn...

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“…8). In contrast, another group of TFs is required for the differentiation but not the survival of BP subtypes, including IRX5 (2), IRX6 (32), and VSX1 (3).…”

Section: Discussionmentioning

confidence: 99%

Transcription factor PRDM8 is required for rod bipolar and type 2 OFF-cone bipolar cell survival and amacrine subtype identity

Jung

Atan

et al. 2015

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

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“…Yet when crossed to generate reciprocal F1 offspring, those F1 strains contain substantially more RBCs than the parental strains, suggesting the presence of variant genes that contribute to the establishment of this trait. A number of transcription factors have been shown to modulate the determination, differentiation, or survival of bipolar cells in the mouse retina, some of which modulate exclusively RBCs (Burmeister et al, 1996 ; Tomita et al, 2000 ; Bramblett et al, 2004 ; Chow et al, 2004 ; Feng et al, 2006 ; Elshatory et al, 2007 ; Shi et al, 2011 , 2012 ; Star et al, 2012 ), raising the possibility that variants within these genes might contribute to such strain differences. Alternatively, other novel genes might contain causal variants discriminating the two parental strains.…”

Section: Introductionmentioning

confidence: 99%

Genetic Control of Rod Bipolar Cell Number in the Mouse Retina

et al. 2018

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Genetic variants modulate the numbers of various retinal cell types in mice. For instance, there is minimal variation in the number of rod bipolar cells (RBCs) in two inbred strains of mice (A/J and C57BL/6J), yet their F1 offspring contain significantly more RBCs than either parental strain. To investigate the genetic source of this variation, we mapped the variation in the number of RBCs across 24 genetically distinct recombinant inbred (RI) strains (the AXB/BXA strain-set), seeking to identify quantitative trait loci (QTL). We then sought to identify candidate genes and potential casual variants at those genomic loci. Variation in RBC number mapped to three genomic loci, each modulating cell number in excess of one-third of the range observed across the RI strains. At each of these loci, we identified candidate genes containing variants that might alter gene function or expression. The latter genes were also analyzed using a transcriptome database, revealing a subset for which expression correlated with variation in RBC number. Using an electroporation strategy, we demonstrate that early postnatal expression of one of them, Ggct (gamma-glutamyl cyclotransferase), modulates bipolar cell number. We identify candidate regulatory variants for this gene, finding a large structural variant (SV) in the putative promoter that reduces expression using a luciferase assay. This SV reducing Ggct expression in vitro is likely the causal variant within the gene associated with the variation in Ggct expression in vivo, implicating it as a quantitative trait variant (QTV) participating in the control of RBC number.

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“…Irx6 also plays a role in the development of bipolar cell subtypes (Star et al, 2012). Co-localization of Irx6 expressing cells with bipolar subtype specific markers demonstrates Irx6 is localized to both type 2 and type 3a bipolar cells (Fig.…”

Section: Irx Genesmentioning

confidence: 92%

The role of homeobox genes in retinal development and disease

Zagozewski

Zhang

Pinto

et al. 2014

Developmental Biology

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Homeobox genes are an evolutionarily conserved class of transcription factors that are critical for development of many organ systems, including the brain and eye. During retinogenesis, homeodomain-containing transcription factors, which are encoded by homeobox genes, play essential roles in the regionalization and patterning of the optic neuroepithelium, specification of retinal progenitors and differentiation of all seven of the retinal cell classes that derive from a common progenitor. Homeodomain transcription factors control retinal cell fate by regulating the expression of target genes required for retinal progenitor cell fate decisions and for terminal differentiation of specific retinal cell types. The essential role of homeobox genes during retinal development is demonstrated by the number of human eye diseases, including colobomas and anophthalmia, which are attributed to homeobox gene mutations. In the following review, we highlight the role of homeodomain transcription factors during retinogenesis and regulation of their gene targets. Understanding the complexities of vertebrate retina development will enhance our ability to drive differentiation of specific retinal cell types towards novel cell-based replacement therapies for retinal degenerative diseases.

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Regulation of retinal interneuron subtype identity by theIroquoishomeobox geneIrx6

Cited by 29 publications

References 42 publications

Transcription factor PRDM8 is required for rod bipolar and type 2 OFF-cone bipolar cell survival and amacrine subtype identity

Transcription factor PRDM8 is required for rod bipolar and type 2 OFF-cone bipolar cell survival and amacrine subtype identity

Genetic Control of Rod Bipolar Cell Number in the Mouse Retina

The role of homeobox genes in retinal development and disease

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