Is Critical for AII Amacrine Cell Production: Selective Bipolar Cell Dependencies and Diminished ERG.

The nuclear factor one (NFI) transcription factor genes , , and are all enriched in late-stage retinal progenitor cells, and their loss has been shown to retain these progenitors at the expense of later-generated retinal cell types. Whether they play any role in the specification of those later-generated fates is unknown, but the expression of one of these, , in a specific amacrine cell type may intimate such a role. Here, conditional knockout (-CKO) mice (both sexes) were assessed, finding a massive and largely selective absence of AII amacrine cells.

Quantitative trait loci on chromosomes 9 and 19 modulate AII amacrine cell number in the mouse retina.

Sequence variants modulating gene function or expression affect various heritable traits, including the number of neurons within a population. The present study employed a forward-genetic approach to identify candidate causal genes and their sequence variants controlling the number of one type of retinal neuron, the AII amacrine cell. Data from twenty-six recombinant inbred (RI) strains of mice derived from the parental C57BL/6J (B6/J) and A/J laboratory strains were used to identify genomic loci regulating cell number.

Neurog2 regulates Isl1 to modulate horizontal cell number.

The population sizes of different retinal cell types vary between different strains of mice, and that variation can be mapped to genomic loci in order to identify its polygenic origin. In some cases, controlling genes act independently, whereas in other instances, they exhibit epistasis. Here, we identify an epistatic interaction revealed through the mapping of quantitative trait loci from a panel of recombinant inbred strains of mice.

Contraction of axonal and dendritic fields in -deficient cone bipolar cells is accompanied by axonal sprouting and dendritic hyper-innervation of pedicles.

Multiple factors regulate the differentiation of neuronal morphology during development, including interactions with afferents, targets, and homotypic neighbors, as well as cell-intrinsic transcriptional regulation. Retinal bipolar cells provide an exemplary model system for studying the control of these processes, as there are 15 transcriptionally and morphologically distinct types, each extending their dendritic and axonal arbors in respective strata within the synaptic layers of the retina. Here we have examined the role of the transcription factor in the control of the morphological differentiation of one type of cone bipolar cell (CBC), the Type 7 cell.

Cell numbers, cell ratios, and developmental plasticity in the rod pathway of the mouse retina.

The precise specification of cellular fate is thought to ensure the production of the correct number of neurons within a population. Programmed cell death may be an additional mechanism controlling cell number, believed to refine the proper ratio of pre- to post-synaptic neurons for a given species. Here, we consider the size of three different neuronal populations in the rod pathway of the mouse retina: rod photoreceptors, rod bipolar cells, and AII amacrine cells.

Interrelationships between Cellular Density, Mosaic Patterning, and Dendritic Coverage of VGluT3 Amacrine Cells.

Amacrine cells of the retina are conspicuously variable in their morphologies, their population demographics, and their ensuing functions. Vesicular glutamate transporter 3 (VGluT3) amacrine cells are a recently characterized type of amacrine cell exhibiting local dendritic autonomy. The present analysis has examined three features of this VGluT3 population, including their density, local distribution, and dendritic spread, to discern the extent to which these are interrelated, using male and female mice.

Straying from the flatfish retinal plan: Cone photoreceptor patterning in the common sole (Solea solea) and the Senegalese sole (Solea senegalensis).

The retinas of nonmammalian vertebrates have cone photoreceptor mosaics that are often organized as highly patterned lattice-like distributions. In fishes, the two main lattice-like patterns are composed of double cones and single cones that are either assembled as interdigitized squares or as alternating rows. The functional significance of such orderly patterning is unknown.

From random to regular: Variation in the patterning of retinal mosaics.

The various types of retinal neurons are each positioned at their respective depths within the retina where they are believed to be assembled as orderly mosaics, in which like-type neurons minimize proximity to one another. Two common statistical analyses for assessing the spatial properties of retinal mosaics include the nearest neighbor analysis, from which an index of their "regularity" is commonly calculated, and the density recovery profile derived from autocorrelation analysis, revealing the presence of an exclusion zone indicative of anti-clustering. While each of the spatial statistics derived from these analyses, the regularity index and the effective radius, can be useful in characterizing such properties of orderly retinal mosaics, they are rarely sufficient for conveying the natural variation in the self-spacing behavior of different types of retinal neurons and the extent to which that behavior generates uniform intercellular spacing across the mosaic.

Vascular changes in diabetic retinopathy-a longitudinal study in the Nile rat.

Diabetic retinopathy is the most common microvascular complication of diabetes and is a major cause of blindness, but an understanding of the pathogenesis of the disease has been hampered by a lack of accurate animal models. Here, we explore the dynamics of retinal cellular changes in the Nile rat (Arvicanthis niloticus), a carbohydrate-sensitive model for type 2 diabetes. The early retinal changes in diabetic Nile rats included increased acellular capillaries and loss of pericytes that correlated linearly with the duration of diabetes.

Modulates Bipolar Cell Number in the Mouse Retina.

The present study interrogated a quantitative trait locus (QTL) on Chr 4 associated with the population sizes of two types of bipolar cell in the mouse retina. This locus was identified by quantifying the number of rod bipolar cells and Type 2 cone bipolar cells across a panel of recombinant inbred (RI) strains of mice derived from two inbred laboratory strains, C57BL/6J (B6/J) and A/J, and mapping a proportion of that variation in cell number, for each cell type, to this shared locus. There, we identified the candidate gene ().

Dopaminergic amacrine cell number, plexus density, and dopamine content in the mouse retina: Strain differences and effects of Bax gene disruption.

Many types of retinal neuron modulate the distribution of their processes to ensure a uniform coverage of the retinal surface. Dendritic field area, for instance, is inversely related to the variation in cellular density for many cell types, observed either across retinal eccentricity or between different strains of mice that differ in cell number. Dopaminergic amacrine (DA) cells, by contrast, have dendritic arbors that bear no spatial relationship to the presence of their immediate homotypic neighbors, yet it remains to be determined whether their coverage upon the retina, as a population, is conserved across variation in their total number.

Bistratified starburst amacrine cells in Sox2 conditional knockout mouse retina display ON and OFF responses.

Cell-intrinsic factors, in conjunction with environmental signals, guide migration, differentiation, and connectivity during early development of neuronal circuits. Within the retina, inhibitory starburst amacrine cells (SBACs) comprise ON types with somas in the ganglion cell layer (GCL) and dendrites stratifying narrowly in the inner half of the inner plexiform layer (IPL) and OFF types with somas in the inner nuclear layer (INL) and dendrites stratifying narrowly in the outer half of the IPL. The transcription factor Sox2 is crucial to this subtype specification.

The somal patterning of the AII amacrine cell mosaic in the mouse retina is indistinguishable from random simulations matched for density and constrained by soma size.

The orderly spacing of retinal neurons is commonly regarded as a characteristic feature of retinal nerve cell populations. Exemplars of this property include the horizontal cells and the cholinergic amacrine cells, where individual cells minimize the proximity to like-type neighbors, yielding regularity in the patterning of their somata. Recently, two types of retinal bipolar cells in the mouse retina were shown to exhibit an order in their somal patterning no different from density-matched simulations constrained by soma size but being otherwise randomly distributed.

Genetic Control of Rod Bipolar Cell Number in the Mouse Retina.

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).

Sox2 regulates astrocytic and vascular development in the retina.

Sox2 is a transcriptional regulator that is highly expressed in retinal astrocytes, yet its function in these cells has not previously been examined. To understand its role, we conditionally deleted Sox2 from the population of astrocytes and examined the consequences on retinal development. We found that Sox2 deletion does not alter the migration of astrocytes, but it impairs their maturation, evidenced by the delayed upregulation of glial fibrillary acidic protein (GFAP) across the retina.

DNER and NFIA are expressed by developing and mature AII amacrine cells in the mouse retina.

The present study has taken advantage of publicly available cell type specific mRNA expression databases in order to identify potential genes participating in the development of retinal AII amacrine cells. We profile two such genes, Delta/Notch-like EGF repeat containing (Dner) and nuclear factor I/A (Nfia), that are each heavily expressed in AII amacrine cells in the mature mouse retina, and which conjointly identify this retinal cell population in its entirety when using antibodies to DNER and NFIA. DNER is present on the plasma membrane, while NFIA is confined to the nucleus, consistent with known functions of each of these two proteins.

Dendritic stratification differs among retinal OFF bipolar cell types in the absence of rod photoreceptors.

Retinal OFF bipolar cells show distinct connectivity patterns with photoreceptors in the wild-type mouse retina. Some types are cone-specific while others penetrate further through the outer plexiform layer (OPL) to contact rods in addition to cones. To explore dendritic stratification of OFF bipolar cells in the absence of rods, we made use of the 'cone-full' Nrl-/- mouse retina in which all photoreceptor precursor cells commit to a cone fate including those which would have become rods in wild-type retinas.

Random spatial patterning of cone bipolar cell mosaics in the mouse retina.

Retinal bipolar cells spread their dendritic arbors to tile the retinal surface, extending them to the tips of the dendritic fields of their homotypic neighbors, minimizing dendritic overlap. Such uniform nonredundant dendritic coverage of these populations would suggest a degree of spatial order in the properties of their somal distributions, yet few studies have examined the patterning in retinal bipolar cell mosaics. The present study examined the organization of two types of cone bipolar cells in the mouse retina, the Type 2 cells and the Type 4 cells, and compared their spatial statistical properties with those of the horizontal cells and the cholinergic amacrine cells, as well as to random simulations of cells matched in density and constrained by soma size.

Genomic Control of Retinal Cell Number: Challenges, Protocol, and Results.

This chapter considers some of the challenges in obtaining accurate and consistent estimates of neuronal population size in the mouse retina, in order to identify the genetic control of cell number through QTL mapping and candidate gene analysis. We first discuss a variety of best practices for analyzing large numbers of recombinant inbred strains of mice over the course of a year in order to amass a satisfactory dataset for QTL mapping. We then consider the relative merits of using average cell density versus estimated total cell number as the target trait to be assessed, and why estimates of heritability may differ for these two traits when studying the retina in whole-mount preparations.

Genomic control of neuronal demographics in the retina.

The mature retinal architecture is composed of various types of neuron, each population differing in size and constrained to particular layers, wherein the cells achieve a characteristic patterning in their local organization. These demographic features of retinal nerve cell populations are each complex traits controlled by multiple genes affecting different processes during development, and their genetic determinants can be dissected by correlating variation in these traits with their genomic architecture across recombinant-inbred mouse strains. Using such a resource, we consider how the variation in the numbers of twelve different types of retinal neuron are independent of one another, including those sharing transcriptional regulation as well as those that are synaptically-connected, each mapping to distinct genomic loci.

Astrocyte structural reactivity and plasticity in models of retinal detachment.

Although retinal neurodegenerative conditions such as age-related macular degeneration, glaucoma, diabetic retinopathy, retinitis pigmentosa, and retinal detachment have different etiologies and pathological characteristics, they also have many responses in common at the cellular level, including neural and glial remodeling. Structural changes in Müller cells, the large radial glia of the retina in retinal disease and injury have been well described, that of the retinal astrocytes remains less so. Using modern imaging technology to describe the structural remodeling of retinal astrocytes after retinal detachment is the focus of this paper.

The patterning of retinal horizontal cells: normalizing the regularity index enhances the detection of genomic linkage.

Retinal neurons are often arranged as non-random distributions called "mosaics," as their somata minimize proximity to neighboring cells of the same type. The horizontal cells serve as an example of such a mosaic, but little is known about the developmental mechanisms that underlie their patterning. To identify genes involved in this process, we have used three different spatial statistics to assess the patterning of the horizontal cell mosaic across a panel of genetically distinct recombinant inbred strains.

Programmed cell death of retinal cone bipolar cells is independent of afferent or target control.

Programmed cell death contributes to the histogenesis of the nervous system, and is believed to be modulated through the sustaining effects of afferents and targets during the period of synaptogenesis. Cone bipolar cells undergo programmed cell death during development, and we confirm that the numbers of three different types are increased when the pro-apoptotic Bax gene is knocked out. When their cone afferents are selectively eliminated, or when the population of retinal ganglion cells is increased, however, cone bipolar cell number remains unchanged.

Design principles and developmental mechanisms underlying retinal mosaics.

Most structures within the central nervous system (CNS) are composed of different types of neuron that vary in both number and morphology, but relatively little is known about the interplay between these two features, i.e. about the population dynamics of a given cell type.

Sox2 regulates cholinergic amacrine cell positioning and dendritic stratification in the retina.

The retina contains two populations of cholinergic amacrine cells, one positioned in the ganglion cell layer (GCL) and the other in the inner nuclear layer (INL), that together comprise ∼1/2 of a percent of all retinal neurons. The present study examined the genetic control of cholinergic amacrine cell number and distribution between these two layers. The total number of cholinergic amacrine cells was quantified in the C57BL/6J and A/J inbred mouse strains, and in 25 recombinant inbred strains derived from them, and variations in their number and ratio (GCL/INL) across these strains were mapped to genomic loci.