scholarly journals Modeling binary and graded cone cell fate patterning in the mouse retina

2020 ◽  
Vol 16 (3) ◽  
pp. e1007691 ◽  
Author(s):  
Kiara C. Eldred ◽  
Cameron Avelis ◽  
Robert J. Johnston ◽  
Elijah Roberts
Keyword(s):  
Cell Fate ◽  
Mouse Retina ◽  
Cone Cell

The Drosophila orphan nuclear receptor seven-up requires the Ras pathway for its function in photoreceptor determination

Development ◽  
1995 ◽  
Vol 121 (1) ◽  
pp. 225-235 ◽  
Author(s):  
G. Begemann ◽  
A.M. Michon ◽  
L. vd Voorn ◽  
R. Wepf ◽  
M. Mlodzik
Keyword(s):  
Cell Fate ◽  
Nuclear Receptor ◽  
Egf Receptor ◽  
Cell Transformation ◽  
Orphan Nuclear Receptor ◽  
Loss Of Function ◽  
Cone Cell ◽  
Ras Pathway ◽  
Protein Levels ◽  
Cone Cells

The Drosophila seven-up (svp) gene specifies outer photoreceptor cell fate in eye development and encodes an orphan nuclear receptor with two isoforms. Transient expression under the sevenless enhancer of either svp isoform leads to a dosage-dependent transformation of cone cells into R7 photoreceptors, and at a lower frequency, R7 cells into outer photoreceptors. To investigate the cellular pathways involved, we have taken advantage of the dosage sensitivity and screened for genes that modify this svp-induced phenotype. We show that an active Ras pathway is essential for the function of both Svp isoforms. Loss-of-function mutations in components of the Ras signal transduction cascade act as dominant suppressors of the cone cell transformation, whilst loss-of-function mutations in negative regulators of Ras-activity act as dominant enhancers. Furthermore, Svp-mediated transformation of cone cells to outer photoreceptors, reminiscent of its wild-type function in specifying R3/4 and R1/6 identity, requires an activated Ras pathway in the same cells, or alternatively dramatic increase in ectopic Svp protein levels. Our results indicate that svp is only fully functional in conjunction with activated Ras. Since we find that mutations in the Egf-receptor are also among the strongest suppressors of svp-mediated cone cell transformation, we propose that the Ras activity in cone cells is due to low level Egfr signaling. Several models that could account for the observed svp regulation by the Ras pathway are discussed.

scholarly journals Modeling binary and graded cone cell fate patterning in the mouse retina

2019 ◽  
Author(s):  
Kiara C. Eldred ◽  
Cameron Avelis ◽  
Robert J. Johnston ◽  
Elijah Roberts
Keyword(s):  
Gene Expression ◽  
Thyroid Hormone ◽  
Cell Fate ◽  
Regulatory Network ◽  
Photoreceptor Cells ◽  
Mouse Retina ◽  
Hormone Signaling ◽  
Cell Fates ◽  
Opsin Expression ◽  
A Cell

AbstractNervous systems are incredibly diverse, with myriad neuronal subtypes defined by gene expression. How binary and graded fate characteristics are patterned across tissues is poorly understood. Expression of opsin photopigments in the cone photoreceptors of the mouse retina provides an excellent model to address this question. Individual cones express S-opsin only, M-opsin, or both S-opsin and M-opsin. These cell populations are patterned along the dorsal-ventral axis, with greater M-opsin expression in the dorsal region and greater S-opsin expression in the ventral region. Thyroid hormone signaling plays a critical role in activating M-opsin and repressing S-opsin. Here, we developed an image analysis approach to identify individual cone cells and evaluate their opsin expression from immunofluorescence imaging tiles spanning roughly 6 mm along the D-V axis of the mouse retina. From analyzing the opsin expression of ∼250,000 cells, we found that cones make a binary decision between S-opsin only and co-expression competent fates. Co-expression competent cells express graded levels of S- and M-opsins, depending nonlinearly on their position in the dorsal-ventral axis. M- and S-opsin expression display differential, inverse patterns. Using these single-cell data we developed a quantitative, stochastic model of cone cell decisions in the retinal tissue based on thyroid hormone signaling activity. The model recovers the probability distribution for cone fate patterning in the mouse retina and describes a minimal set of interactions that are necessary to reproduce the observed cell fates. Our study provides a paradigm describing how differential responses to regulatory inputs generate complex patterns of binary and graded cell fates.Author SummaryThe development of a cell in a mammalian tissue is governed by a complex regulatory network that responds to many input signals to give the cell a distinct identity, a process referred to as cell-fate specification. Some of these cell fates have binary on-or-off gene expression patterns, while others have graded gene expression that changes across the tissue. Differentiation of the photoreceptor cells that sense light in the mouse retina provides a good example of this process. Here, we explore how complex patterns of cell fates are specified in the mouse retina by building a computational model based on analysis of a large number of photoreceptor cells from microscopy images of whole retinas. We use the data and the model to study what exactly it means for a cell to have a binary or graded cell fate and how these cell fates can be distinguished from each other. Our study shows how tens-of-thousands of individual photoreceptor cells can be patterned across a complex tissue by a regulatory network, creating a different outcome depending upon the received inputs.

scholarly journals MicroRNA Signatures of the Developing Primate Fovea

2021 ◽  
Vol 9 ◽  
Author(s):  
Elizabeth S. Fishman ◽  
Mikaela Louie ◽  
Adam M. Miltner ◽  
Simranjeet K. Cheema ◽  
Joanna Wong ◽  
...  
Keyword(s):  
Rhesus Monkey ◽  
Cell Fate ◽  
Molecular Mechanisms ◽  
Color Discrimination ◽  
Light Sensitivity ◽  
Human Vision ◽  
Mouse Retina ◽  
Mirna Cluster ◽  
Cone Photoreceptors ◽  
Specialized Region

Rod and cone photoreceptors differ in their shape, photopigment expression, synaptic connection patterns, light sensitivity, and distribution across the retina. Although rods greatly outnumber cones, human vision is mostly dependent on cone photoreceptors since cones are essential for our sharp visual acuity and color discrimination. In humans and other primates, the fovea centralis (fovea), a specialized region of the central retina, contains the highest density of cones. Despite the vast importance of the fovea for human vision, the molecular mechanisms guiding the development of this region are largely unknown. MicroRNAs (miRNAs) are small post-transcriptional regulators known to orchestrate developmental transitions and cell fate specification in the retina. Here, we have characterized the transcriptional landscape of the developing rhesus monkey retina. Our data indicates that non-human primate fovea development is significantly accelerated compared to the equivalent retinal region at the other side of the optic nerve head, as described previously. Notably, we also identify several miRNAs differentially expressed in the presumptive fovea, including miR-15b-5p, miR-342-5p, miR-30b-5p, miR-103-3p, miR-93-5p as well as the miRNA cluster miR-183/-96/-182. Interestingly, miR-342-5p is enriched in the nasal primate retina and in the peripheral developing mouse retina, while miR-15b is enriched in the temporal primate retina and increases over time in the mouse retina in a central-to-periphery gradient. Together our data constitutes the first characterization of the developing rhesus monkey retinal miRNome and provides novel datasets to attain a more comprehensive understanding of foveal development.

scholarly journals Regulation of neurogenesis and gliogenesis by the matricellular protein CCN2 in the mouse retina

2021 ◽  
Author(s):  
Golam Mohiuddin ◽  
Genesis Lopez ◽  
Jose Sinon ◽  
M. Elizabeth Hartnett ◽  
Anastasiia Bulakhova ◽  
...  
Keyword(s):  
Glial Cell ◽  
Cell Fate ◽  
Matrix Protein ◽  
Ex Vivo ◽  
Mouse Genetics ◽  
Extracellular Matrix Protein ◽  
Retinal Cell ◽  
Mouse Retina ◽  
Matricellular Protein ◽  
Retinal Progenitor

AbstractCellular communication network (CCN) 2 is an extracellular matrix protein with cell type- and context-dependent functions. Using a combination of mouse genetics and omic approaches, we show that CCN2 is expressed in early embryonic retinal progenitor cells (RPCs) and becomes restricted to fully differentiated Müller glial cells (MGCs) thereafter. Germline deletion of CCN2 in mice decreases BrdU labeling, reduces RPC pool, and impairs the competency of remaining RPCs to generate early and late born retinal cell types. Retinal hypocellularity and microphthalmia ensue. The transcriptomic changes associated with CCN2 inactivation include reduced marker and transcriptional regulator genes of retinal ganglion cells, photoreceptors and MGCs. Yap (Yes-associated protein), a singular node for transcriptional regulation of growth and differentiation genes, is also a target of CCN2 signals. In an organotypic model of ex vivo cultured embryonic retinas, CCN2 and YAP immunoreactivity signals overlap. Lentivirus-mediated YAP expression in CCN2-deficient retinal explants increases the number of differentiating Sox9-positive MGCs. Taken together, our data indicate that CCN2 controls the proliferative and differentiation potentials of RPCs ultimately endowing, a subpopulation thereof, with Müller glial cell fate.Summary statementA CCN2-YAP regulatory axis controls retinal progenitor cell growth and lineage commitment to neuronal and glial cell fates.

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.

Glial cell fate specification modulated by the bHLH gene Hes5 in mouse retina

Development ◽  
2000 ◽  
Vol 127 (12) ◽  
pp. 2515-2522 ◽  
Author(s):  
M. Hojo ◽  
T. Ohtsuka ◽  
N. Hashimoto ◽  
G. Gradwohl ◽  
F. Guillemot ◽  
...  
Keyword(s):  
Glial Cell ◽  
Cell Fate ◽  
Glial Cells ◽  
Expression Patterns ◽  
Cell Number ◽  
Current Data ◽  
Mouse Retina ◽  
Cell Fate Specification ◽  
Bhlh Gene ◽  
Fate Specification

Neurons and glial cells differentiate from common precursors. Whereas the gene glial cells missing (gcm) determines the glial fate in Drosophila, current data about the expression patterns suggest that, in mammals, gcm homologues are unlikely to regulate gliogenesis. Here, we found that, in mouse retina, the bHLH gene Hes5 was specifically expressed by differentiating Muller glial cells and that misexpression of Hes5 with recombinant retrovirus significantly increased the population of glial cells at the expense of neurons. Conversely, Hes5-deficient retina showed 30–40% decrease of Muller glial cell number without affecting cell survival. These results indicate that Hes5 modulates glial cell fate specification in mouse retina.

rugose (rg), a Drosophila A kinase Anchor Protein, Is Required for Retinal Pattern Formation and Interacts Genetically With Multiple Signaling Pathways

Genetics ◽  
2002 ◽  
Vol 161 (2) ◽  
pp. 693-710
Author(s):  
Hoda K Shamloula ◽  
Mkajuma P Mbogho ◽  
Angel C Pimentel ◽  
Zosia M A Chrzanowska-Lightowlers ◽  
Vanneta Hyatt ◽  
...  
Keyword(s):  
Pattern Formation ◽  
Signaling Pathways ◽  
Cell Fate ◽  
Genetic Interaction ◽  
Cell Phenotype ◽  
Cell Fate Determination ◽  
Cone Cell ◽  
Anchor Protein ◽  
Fate Determination ◽  
Cone Cells

Abstract In the developing Drosophila eye, cell fate determination and pattern formation are directed by cell-cell interactions mediated by signal transduction cascades. Mutations at the rugose locus (rg) result in a rough eye phenotype due to a disorganized retina and aberrant cone cell differentiation, which leads to reduction or complete loss of cone cells. The cone cell phenotype is sensitive to the level of rugose gene function. Molecular analyses show that rugose encodes a Drosophila A kinase anchor protein (DAKAP 550). Genetic interaction studies show that rugose interacts with the components of the EGFR- and Notch-mediated signaling pathways. Our results suggest that rg is required for correct retinal pattern formation and may function in cell fate determination through its interactions with the EGFR and Notch signaling pathways.

STAT3-Mediated Signaling in the Determination of Rod Photoreceptor Cell Fate in Mouse Retina

2004 ◽  
Vol 45 (7) ◽  
pp. 2407 ◽  
Author(s):  
Samuel Shao-Min Zhang ◽  
Jiye Wei ◽  
Hua Qin ◽  
Lixin Zhang ◽  
Bing Xie ◽  
...  
Keyword(s):  
Cell Fate ◽  
Photoreceptor Cell ◽  
Mouse Retina ◽  
Rod Photoreceptor

Centrosome Aurora A gradient ensures single polarity axis in C. elegans embryos

2020 ◽  
Vol 48 (3) ◽  
pp. 1243-1253 ◽  
Author(s):  
Sukriti Kapoor ◽  
Sachin Kotak
Keyword(s):  
Symmetry Breaking ◽  
Cell Fate ◽  
Cell Cortex ◽  
Axis Formation ◽  
Aurora A Kinase ◽  
Aurora A ◽  
C Elegans ◽  
Cell Embryo ◽  
Polarity Establishment

Cellular asymmetries are vital for generating cell fate diversity during development and in stem cells. In the newly fertilized Caenorhabditis elegans embryo, centrosomes are responsible for polarity establishment, i.e. anterior–posterior body axis formation. The signal for polarity originates from the centrosomes and is transmitted to the cell cortex, where it disassembles the actomyosin network. This event leads to symmetry breaking and the establishment of distinct domains of evolutionarily conserved PAR proteins. However, the identity of an essential component that localizes to the centrosomes and promotes symmetry breaking was unknown. Recent work has uncovered that the loss of Aurora A kinase (AIR-1 in C. elegans and hereafter referred to as Aurora A) in the one-cell embryo disrupts stereotypical actomyosin-based cortical flows that occur at the time of polarity establishment. This misregulation of actomyosin flow dynamics results in the occurrence of two polarity axes. Notably, the role of Aurora A in ensuring a single polarity axis is independent of its well-established function in centrosome maturation. The mechanism by which Aurora A directs symmetry breaking is likely through direct regulation of Rho-dependent contractility. In this mini-review, we will discuss the unconventional role of Aurora A kinase in polarity establishment in C. elegans embryos and propose a refined model of centrosome-dependent symmetry breaking.

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