Epigenetic mechanisms that regulate cell identity

Individual cell fate decisions can vary according to changes in gene expression in response to environmental, developmental, or metabolic cues. This plasticity is tightly regulated during embryonic development and mediated by the exquisitely coordinated activation and repression of groups of genes. Genes that become repressed are immersed in a condensed chromatin environment that renders them refractory to stimulation. This mechanism is responsible for both the loss of cell plasticity during differentiation and the preservation of cell identity. Understanding the molecular events involved in the establishment and maintenance of these restrictive domains will benefit the design of strategies for cellular reprogramming, differentiation, and cancer treatment.     

Environmental enrichment effects on development of retinal ganglion cell dendritic stratification require retinal BDNF

A well-known developmental event of retinal maturation is the progressive segregation of retinal ganglion cell (RGC) dendrites into a and b sublaminae of the inner plexiform layer (IPL), a morphological rearrangement crucial for the emergence of the ON and OFF pathways. The factors regulating this process are not known, although electrical activity has been demonstrated to play a role. Here we report that Environmental Enrichment (EE) accelerates the developmental segregation of RGC dendrites and prevents the effects exerted on it by dark rearing (DR). Development of RGC stratification was analyzed in a line of transgenic mice expressing plasma-membrane marker green fluorescent protein (GFP) under the control of Thy-1 promoter; we visualized the a and b sublaminae of the IPL by using an antibody selectively directed against a specific marker of cholinergic neurons. EE precociously increases Brain Derived Neurotrophic Factor (BDNF) in the retina, in parallel with the precocious segregation of RGC dendrites; in addition, EE counteracts retinal BDNF reduction in DR retinas and promotes a normal segregation of RGC dendrites. Blocking retinal BDNF by means of antisense oligos blocks EE effects on the maturation of RGC dendritic stratification. Thus, EE affects the development of RGC dendritic segregation and retinal BDNF is required for this effect to take place, suggesting that BDNF could play an important role in the emergence of the ON and OFF pathways.     

Properties of mouse retinal ganglion cell dendritic growth during postnatal development

The property of dendritic growth dynamics during development is a subject of intense interest. Here, we investigated the dendritic motility of retinal ganglion cells (RGCs) during different developmental stages, using ex vivo mouse retina explant culture, Semliki Forest Virus transfection and time-lapse observations. The results illustrated that during development, the dendritic motility underwent a change from rapid growth to a relatively stable state, i.e., at P0 (day of birth), RGC dendrites were in a highly active state, whereas at postnatal 13 (P13) they were more stable, and at P3 and P8, the RGCs were in an intermediate state. At any given developmental stage, RGCs of different types displayed the same dendritic growth rate and extent. Since the mouse is the most popular mammalian model for genetic manipulation, this study provided a methodological foundation for further exploring the regulatory mechanisms of dendritic development.     

Asymmetrical dendritic fields of retinal ganglion cells

By use of Golgi chrome—silver impregnation, studies were made of the dendritic branchings of feline and frog ganglion cells. It was shown that besides the known varieties of ganglion cells there were asymmetrical neurones whose dendrites lay all to one side. Essential differences distinguished these ganglion cells in the cat from those in the frog, differences depending upon the architectonics of the inner plexiform layer, which is broad and subdivided into layers in the frog, and narrow in the cat. We discuss the possible role of neurones with a unilateral arrangement of dendrites in relation to know electrophysiological data on retinal detectors and the receptive fields of ganglion cells.Brain Institute, Academy of Medical Sciences of the USSR, Moscow. Translated from Neirofiziologiya, Vol. 3, No. 3, pp. 301–307, May–June, 1971.     

Developmental retinal ganglion cell death and retinotopicity of the murine retinocollicular projection

During mammalian visual system development, retinal ganglion cells (RGCs) undergo extensive apoptotic death. In mouse retina, approximately 50% of RGCs present at birth (postnatal day 0; P0) die by P5, at a time when axons innervate central targets such as the superior colliculus (SC). We examined whether RGCs that make short‐range axonal targeting errors within the contralateral SC are more likely to be eliminated during the peak period of RGC death (P1‐P5), compared with RGCs initially making more accurate retinotopic connections. A small volume (2.3 nL) of the retrograde nucleophilic dye Hoechst 33342 was injected into the superficial left SC of anesthetized neonatal C57Bl/6J mice at P1 (n = 5) or P4 (n = 8), and the contralateral retina wholemounted 12 hr later. Retrogradely labelled healthy and dying (pyknotic) RGCs were identified by morphological criteria and counted. The percentage of pyknotic RGCs was analyzed in relation to distance from the area of highest density RGC labelling, presumed to represent the most topographically accurate population. As expected, pyknotic RGC density at P1 was significantly greater than P4 (p < 0.05). At P4, the density of healthy RGCs 500–750 µm away from the central region was significantly less, although this was not reflected in altered pyknotic rates. However, at P1 there was a trend (p = 0.08) for an increased proportion of pyknotic RGCs, specifically in temporal parts of the retina outside the densely labelled center. Overall, the lack of consistent association between short‐range targeting errors and cell death suggests that most postnatal RGC loss is not directly related to topographic accuracy. © 2017 Wiley Periodicals, Inc. Develop Neurobiol 78: 51–60, 2018     

Quantitative analysis of dendritic morphology of the alpha and delta retinal ganglion cells in the rat: A cell classification study

Type I retinal ganglion cells in the rat have been classified into several groups based on the cell body size and dendritic morphology. Considerable overlap and heterogeneity within groups have been reported, which is especially obvious for the morphology of the dendritic tree. For that purpose, we analysed quantitatively the dendritic morphology of the alpha and delta rat retinal ganglion cells, using parameters which provide information on the dendritic field size, shape of the dendritic tree and dendritic branching complexity. We show that the alpha and delta cells have significantly different dendritic field sizes. Taking into account the level of stratification of the dendritic tree, we found a difference in the properties of the dendritic morphology between alpha inner and alpha outer cells, while the opposite result was obtained for the delta inner and delta outer delta cells. In this study we also call attention to the relationship between morphological parameters and retinal eccentricity. The significance of our quantitative results in terms of present alpha and delta rat retinal ganglion cell classification is discussed.     

Receptor protein tyrosine phosphatases regulate retinal ganglion cell axon outgrowth in the developing Xenopus visual system

Receptor protein tyrosine phosphatases (RPTPs) are regulators of axon outgrowth and guidance in a variety of different vertebrate and invertebrate systems. Three RPTPs, CRYP-alpha, PTP-delta, and LAR, are expressed in overlapping but distinct patterns in the developing Xenopus retina, including expression in retinal ganglion cells (RGCs) as they send axons to the tectum (Johnson KG, Holt CE. 2000. Expression of CRYP-alpha, LAR, PTP-delta, and PTP-rho in the developing Xenopus visual system. Mech Dev 92:291-294). In order to examine the role of these RPTPs in visual system development, putative dominant negative RPTP mutants (CS-CRYP-alpha, CS-PTP-delta, and CS-LAR) were expressed either singly or in combination in retinal cells. No effect was found on either retinal cell fate determination or on gross RGC axon guidance to the tectum. However, expression of these CS-RPTP constructs differentially affected the rate of RGC axon outgrowth. In vivo, expression of all three CS-RPTPs or CS-PTP-delta alone inhibited RGC axon outgrowth, while CS-LAR and CS-CRYP-alpha had no significant effect. In vitro, expression of CS-CRYP-alpha enhanced neurite outgrowth, while CS-PTP-delta inhibited neurite outgrowth in a substrate-dependent manner. This study provides the first in vivo evidence that RPTPs regulate retinal axon outgrowth.     

Receptive field microstructure and dendritic geometry of retinal ganglion cells

We studied the fine spatial structure of the receptive fields of retinal ganglion cells and its relationship to the dendritic geometry of these cells. Cells from which recordings had been made were microinjected with Lucifer yellow, so that responses generated at precise locations within the receptive field center could be directly compared with that cell's dendritic structure. While many cells with small receptive fields had domeshaped sensitivity profiles, the majority of large receptive fields were composed of multiple regions of high sensitivity. The density of dendritic branches at any one location did not predict the regions of high sensitivity. Instead, the interactions between a ganglion cell's dendritic tree and the local mosaic of bipolar cell axons seem to define the fine structure of the receptive field center.     

MicroRNAs regulate dendritic cell differentiation and function

MicroRNAs (miRNAs) are an important class of cellular regulators that modulate gene expression and thereby influence cell fate and function. In the immune system, miRNAs act at checkpoints during hematopoietic development and cell subset differentiation, they modulate effector cell function, and they are implicated in the maintenance of homeostasis. Dendritic cells (DCs), the professional APCs involved in the coordination of adaptive immune responses, are also regulated by miRNAs. Some DC-relevant miRNAs, including miR-155 and miR-146a, are shared with other immune cells, whereas others have been newly identified. In this review, we summarize the current understanding of where miRNAs are active during DC development from myeloid precursors and differentiation into specialized subsets, and which miRNAs play roles in DC function.     

GABAergic neurotransmission and retinal ganglion cell function

Ganglion cells are the output retinal neurons that convey visual information to the brain. There are ~20 different types of ganglion cells, each encoding a specific aspect of the visual scene as spatial and temporal contrast, orientation, direction of movement, presence of looming stimuli; etc. Ganglion cell functioning depends on the intrinsic properties of ganglion cell’s membrane as well as on the excitatory and inhibitory inputs that these cells receive from other retinal neurons. GABA is one of the most abundant inhibitory neurotransmitters in the retina. How it modulates the activity of different types of ganglion cells and what is its significance in extracting the basic features from visual scene are questions with fundamental importance in visual neuroscience. The present review summarizes current data concerning the types of membrane receptors that mediate GABA action in proximal retina; the effects of GABA and its antagonists on the ganglion cell light-evoked postsynaptic potentials and spike discharges; the action of GABAergic agents on centre-surround organization of the receptive fields and feature related ganglion cell activity. Special emphasis is put on the GABA action regarding the ON–OFF and sustained–transient ganglion cell dichotomy in both nonmammalian and mammalian retina.     

The autoregulation of retinal ganglion cell number

The development of the nervous system is dependent on a complex set of signals whose precise co-ordination ensures that the correct number of neurones are generated. This regulation is achieved through a variety of cues that influence both the generation and the maintenance of neurones during development. We show that in the chick embryo, stratified retinal ganglion cells (RGCs) are themselves responsible for providing the signals that control the number of RGCs that are generated, both by inhibiting the generation of new ganglion cells and by killing incoming migratory ganglion cells. Selective toxicological ablation of RGCs in the chick embryo resulted in the achronic generation of ganglion cells, which eventually led to the repopulation of the ganglion cell layer and a large decrease in the physiological cell death affecting postmitotic migratory neurones. Interestingly, the application of exogenous NGF reversed the effects of ganglion cell ablation on ganglion cell death. Because the only source of NGF in the retina is that produced by the stratified ganglion cells, we infer that these differentiated neurones regulate their own cell number by secreting NGF, a neurotrophin that has previously been shown to be responsible for the death of migrating ganglion cells.