scholarly journals Essential functions of MLL1 and MLL2 in retinal development and cone cell maintenance

2021 ◽  
Author(s):  
Chi Sun ◽  
Xiaodong Zhang ◽  
Philip Andrew Ruzycki ◽  
Shiming Chen
Keyword(s):  
Cell Fate ◽  
Retinal Development ◽  
Horizontal Cell ◽  
Conditional Knockout ◽  
Mouse Retina ◽  
Light Responses ◽  
Photoreceptor Outer Segments ◽  
Similar Phenotype ◽  
Progenitor Cell Proliferation ◽  
Cell Maintenance

MLL1 (KMT2A) and MLL2 (KMT2B) are homologous members of the mixed-lineage leukemia (MLL) family of histone methyltransferases involved in epigenomic transcriptional regulation. Their sequence variants have been associated with neurological and psychological disorders, but little is known about their roles and mechanism of action in CNS development. Using mouse retina as a model, we previously reported the roles of MLL1 in retinal neurogenesis and horizontal cell maintenance. Here we determine roles of MLL2 and MLL1/MLL2 together in retinal development using conditional knockout (CKO) mice. Deleting Mll2 from Chx10+ retinal progenitors resulted in a similar phenotype as Mll1 CKO, but removal of both alleles produced much more severe deficits than each single CKO: 1-month double CKO mutants displayed null light responses in electroretinogram; thin retinal layers, including shorter photoreceptor outer segments with impaired phototransduction gene expression; and reduced numbers of M-cones, horizontal and amacrine neurons, followed by fast retinal degeneration. Despite moderately reduced progenitor cell proliferation at P0, the neurogenic capacity was largely maintained in double CKO mutants. However, upregulated apoptosis and reactive gliosis were detected during postnatal retinal development. Finally, the removal of both MLLs in fated rods produced a normal phenotype, but the CKO in M-cones impaired M-cone function and survival, indicating both cell non-autonomous and autonomous mechanisms. Altogether, our results suggest that MLL1/MLL2 play redundant roles in maintaining specific retinal neurons after cell fate specification and are essential for establishing functional neural networks.

scholarly journals Rod and Cone Contributions to Horizontal Cell Light Responses in the Mouse Retina

2008 ◽  
Vol 28 (27) ◽  
pp. 6818-6825 ◽  
Author(s):  
J. Trumpler ◽  
K. Dedek ◽  
T. Schubert ◽  
L. P. de Sevilla Muller ◽  
M. Seeliger ◽  
...  
Keyword(s):  
Horizontal Cell ◽  
Mouse Retina ◽  
Light Responses

scholarly journals Functional Roles of Otx2 Transcription Factor in Postnatal Mouse Retinal Development

2007 ◽  
Vol 27 (23) ◽  
pp. 8318-8329 ◽  
Author(s):  
Chieko Koike ◽  
Akihiro Nishida ◽  
Shinji Ueno ◽  
Hiromitsu Saito ◽  
Rikako Sanuki ◽  
...  
Keyword(s):  
Cell Fate ◽  
Bipolar Cell ◽  
Functional Role ◽  
Retinal Development ◽  
Terminal Differentiation ◽  
Cell Development ◽  
Bipolar Cells ◽  
Conditional Knockout ◽  
Retinal Bipolar Cells

ABSTRACT We previously reported that Otx2 is essential for photoreceptor cell fate determination; however, the functional role of Otx2 in postnatal retinal development is still unclear although it has been reported to be expressed in retinal bipolar cells and photoreceptors at postnatal stages. In this study, we first examined the roles of Otx2 in the terminal differentiation of photoreceptors by analyzing Otx2; Crx double-knockout mice. In Otx2 +/−; Crx −/− retinas, photoreceptor degeneration and downregulation of photoreceptor-specific genes were much more prominent than in Crx −/− retinas, suggesting that Otx2 has a role in the terminal differentiation of the photoreceptors. Moreover, bipolar cells decreased in the Otx2 +/−; Crx −/− retina, suggesting that Otx2 is also involved in retinal bipolar-cell development. To further investigate the role of Otx2 in bipolar-cell development, we generated a postnatal bipolar-cell-specific Otx2 conditional-knockout mouse line. Immunohistochemical analysis of this line showed that the expression of protein kinase C, a marker of mature bipolar cells, was significantly downregulated in the retina. Electroretinograms revealed that the electrophysiological function of retinal bipolar cells was impaired as a result of Otx2 ablation. These data suggest that Otx2 plays a functional role in the maturation of retinal photoreceptor and bipolar cells.

Reorganization of horizontal cell processes in the developing FVB/N mouse retina

2001 ◽  
Vol 306 (2) ◽  
pp. 341-346 ◽  
Author(s):  
Sung-Jin Park ◽  
In-Beom Kim ◽  
Kyu-Ryong Choi ◽  
Jung-Il Moon ◽  
Su-Ja Oh ◽  
...  
Keyword(s):  
Horizontal Cell ◽  
Mouse Retina ◽  
Cell Processes

scholarly journals Chromatin accessibility analysis reveals regulatory dynamics of developing human retina and hiPSC-derived retinal organoids

2020 ◽  
Vol 6 (6) ◽  
pp. eaay5247 ◽  
Author(s):  
Haohuan Xie ◽  
Wen Zhang ◽  
Mei Zhang ◽  
Tasneem Akhtar ◽  
Young Li ◽  
...  
Keyword(s):  
Transcriptional Regulatory Network ◽  
Retinal Development ◽  
Chromatin Accessibility ◽  
Mouse Retina ◽  
Transcriptional Dynamics ◽  
Transcriptional Regulatory ◽  
Regulatory Dynamics ◽  
Induced Pluripotent

Retinal organoids (ROs) derived from human induced pluripotent stem cells (hiPSCs) provide potential opportunities for studying human retinal development and disorders; however, to what extent ROs recapitulate the epigenetic features of human retinal development is unknown. In this study, we systematically profiled chromatin accessibility and transcriptional dynamics over long-term human retinal and RO development. Our results showed that ROs recapitulated the human retinogenesis to a great extent, but divergent chromatin features were also discovered. We further reconstructed the transcriptional regulatory network governing human and RO retinogenesis in vivo. Notably, NFIB and THRA were identified as regulators in human retinal development. The chromatin modifications between developing human and mouse retina were also cross-analyzed. Notably, we revealed an enriched bivalent modification of H3K4me3 and H3K27me3 in human but not in murine retinogenesis, suggesting a more dedicated epigenetic regulation on human genome.

Dual effect of glycine on horizontal cells of the tiger salamander retina

1991 ◽  
Vol 66 (6) ◽  
pp. 1993-2001 ◽  
Author(s):  
S. Borges ◽  
M. Wilson
Keyword(s):  
Opposite Effect ◽  
Horizontal Cell ◽  
Light Response ◽  
Membrane Resistance ◽  
Horizontal Cells ◽  
Field Size ◽  
Dual Effect ◽  
Light Responses ◽  
Low Concentrations ◽  
High Concentrations

1. The effects of glycine on horizontal cells have been examined by microelectrode recording from superfused retinas isolated from the salamander. 2. Low concentrations of glycine (less than 50 microM) hyperpolarized horizontal cells and increased the magnitude of their light responses. Millimolar concentrations produced the opposite effect of depolarizing these cells and reducing their light response amplitudes. 3. In the presence of Co2+ and Mg2+ at concentrations sufficient to suppress the light response, millimolar glycine still exerted a depolarizing effect on horizontal cells, implying that this effect was largely a direct one on horizontal cell membranes. 4. Although both the rod and the cone contributions to horizontal cell light responses were reduced by millimolar glycine, rod input was reduced more, suggesting that millimolar glycine may also exert a presynaptic effect. 5. Strychnine (10 microns) antagonized the effects of millimolar glycine and, in the absence of exogenously applied glycine, caused horizontal cells to hyperpolarize and their light responses to increase in amplitude. This result implies that, in darkness, glycine is tonically released onto horizontal cells and maintains them in a state of partial depolarization. 6. The low-concentration effect of glycine was accompanied by an increased membrane resistance and receptive field size but no change in the balance of rod and cone input. 7. Low concentrations of glycine were often seen to cause a speeding of light responses, whereas high concentrations sometimes caused a slowing of response kinetics. Response kinetics were found to correlate with horizontal cell dark membrane potential so that, positive to -30 mV, depolarization slowed responses whereas kinetics at more negative values were largely independent of voltage.

scholarly journals Voltage-clamp recordings of light responses from wild-type and mutant mouse cone photoreceptors

2019 ◽  
Vol 151 (11) ◽  
pp. 1287-1299 ◽  
Author(s):  
Norianne T. Ingram ◽  
Alapakkam P. Sampath ◽  
Gordon L. Fain
Keyword(s):  
Voltage Clamp ◽  
Mouse Retina ◽  
Cone Photoreceptors ◽  
Wild Type ◽  
Light Responses ◽  
Α Subunit ◽  
Background Light ◽  
Connexin 36 ◽  
Mouse Lines

We describe the first extensive study of voltage-clamp current responses of cone photoreceptors in unlabeled, dark-adapted mouse retina using only the position and appearance of cone somata as a guide. Identification was confirmed from morphology after dye filling. Photocurrents recorded from wild-type mouse cones were biphasic with a fast cone component and a slower rod component. The rod component could be eliminated with dim background light and was not present in mouse lines lacking the rod transducin-α subunit (Gnat1−/−) or connexin 36 (Cx36−/−). Cones from Gnat1−/− or Cx36−/− mice had resting membrane potentials between −45 and −55 mV, peak photocurrents of 20–25 picoamps (pA) at a membrane potential Vm = −50 mV, sensitivities 60–70 times smaller than rods, and a total membrane capacitance two to four times greater than rods. The rate of activation (amplification constant) was largely independent of the brightness of the flash and was 1–2 s−2, less than half that of rods. The role of Ca2+-dependent transduction modulation was investigated by recording from cones in mice lacking rod transducin (Gnat1), recoverin, and/or the guanylyl-cyclase–activating proteins (GCAPs). In confirmation of previous results, responses of Gnat1−/−;Gcaps−/− cones and triple-mutant Gnat1−/−;Gcaps−/−;Rv−/− cones recovered more slowly both to light flashes and steps and were more sensitive than cones expressing the GCAPs. Cones from all four mouse lines showed significant recovery and escaped saturation even in bright background light. This recovery occurred too rapidly to be caused by pigment bleaching or metaII decay and appears to reflect some modulation of response inactivation in addition to those produced by recoverin and the GCAPs. Our experiments now make possible a more detailed understanding of the cellular physiology of mammalian cone photoreceptors and the role of conductances in the inner and outer segment in producing cone light responses.

PRCD is Concentrated at the Base of Photoreceptor Outer Segments and is Involved in Outer Segment Disc Formation

2019 ◽  
Author(s):  
Gilad Allon ◽  
Irit Mann ◽  
Lital Remez ◽  
Elisabeth Sehn ◽  
Leah Rizel ◽  
...  
Keyword(s):  
Retinal Degeneration ◽  
Knockout Mice ◽  
Outer Segment ◽  
Mouse Retina ◽  
Cone Photoreceptors ◽  
Photoreceptor Outer Segment ◽  
Photoreceptor Outer Segments ◽  
Outer Segments ◽  
Rod And Cone Photoreceptors ◽  
Disc Formation

Abstract Mutations of the PRCD gene are associated with rod-cone degeneration in both dogs and humans. Prcd is expressed in the mouse eye as early as embryonic day 14. In the adult mouse retina PRCD is expressed in the outer segments of both rod and cone photoreceptors. Immunoelectron microscopy revealed that PRCD is located at the outer segment rim, and that it is highly concentrated at the base of the outer segment. Prcd-knockout mice present with progressive retinal degeneration, starting at 20 weeks of age and onwards. This process is reflected by a significant and progressive reduction of both scotopic and photopic electroretinographic responses, and by thinning of the retina, and specifically of the outer nuclear layer, indicating photoreceptor loss. Electron microscopy revealed severe damage to photoreceptor outer segments, which is associated with immigration of microglia cells to the Prcd-knockout retina, and accumulation of vesicles in the inter-photoreceptor space. Phagocytosis of photoreceptor outer segment discs by the retinal pigmented epithelium is severely reduced. Our data show that Prcd-knockout mice serve as a good model for retinal degeneration caused by PRCD mutations in humans. Our findings in these mice support the involvement of PRCD in outer segment disc formation of both rod and cone photoreceptors. Furthermore, they suggest a feedback mechanism which coordinates the rate of photoreceptor outer segment disc formation, shedding and phagocytosis. This study has important implications for understanding the function of PRCD in the retina, as well as for future development of treatment modalities for PRCD-deficiency in humans.

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