权益分类	功能权益	普通用户	{{item.name}}会员
{{category.name}}	{{benefitItem.name}}

The roles of LIM-Homeodomain Transcription Factors in Retinal Development

LIM-同源域转录因子在视网膜发育中的作用

基本信息

批准号：
10116905
负责人：
Lin Gan
金额：
$ 38.38万
依托单位：
AUGUSTA UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-03-01 至 2022-02-28
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10116905
关键词：
Amacrine Cells Axon Blindness Cell Differentiation process Cell Lineage Cells Characteristics Contrast Sensitivity Coupled Data Dendrites Detection Development Dyes Electrophysiology (science)Enterobacteria phage P1 Cre recombinase Event Failure Family Ganglia Ganglion Cell Layer Genes Genetic Genetic Transcription Individual Injections Inner Nuclear Layer Inner Plexiform Layer Knock-in LHX2 gene Link Location Massive Parallel Sequencing Mediating Molecular Morphology Mus Nervous system structure Neuraxis Neurons Pathway interactions Pattern Photoreceptors Play Process Property Proteins Regulatory Pathway Reporter Retina Retinal Cone Retinal Defect Role Shotgun Sequencing Stratification Structure Subgroup Synapses Technology Vision Visual Perception Visual impairment base cell type chromatin immunoprecipitation homeodomain in vivo interest member neural circuit novel null mutation object motion patch clamp public health relevance retinal neuron retinal rods retinogenesis transcription factor transcriptome transcriptome sequencing visual information visual processing

项目摘要

DESCRIPTION (provided by applicant): Our accurate vision depends on the flow of visual information through precisely wired synaptic connections among axons and dendrites of retinal neurons with unique morphological and functional properties. In the vertebrate retina, each of the six neuronal cell types: ganglion, amacrine, bipolar, horizontal, and rod and cone photoreceptor cells are further divided into subtypes based on location, morphology and function. Of all retinal neurons, amacrine cells are the most diverse group with >30 subtypes being identified so far. They represent ~40% of neurons both in the inner nuclear layer (INL) and the ganglion cell layer (GCL), make up a majority of synapses in the inner plexiform layer (IPL), and contribute to a majority of visual processing in the retina. One of the key questions i how the many retinal neuronal subtypes are produced and wired during development. In this proposal, we focus on the amacrine cells associated with the sublaminar layer 3 (S3) of the IPL. The S3 sublamina separates the ON and OFF laminas in the IPL but its cellular makeup and function is poorly understood. Here, we have demonstrated LHX9, a LIM-homeodomain transcription factor, is expressed early in retinogenesis and its expression is tightly confined toa few amacrine cells in the INL and the GCL. In our preliminary study, we have shown that these LHX9+ cells are a subgroup of GABAergic amacrine cells and express GAD67 but not GAD65. LHX9-expressing cells are also LHX2-expressing subgroup of amacrine cells. Targeted deletion of Lhx9 in mice results in a nearly complete loss of these LHX2-expressing amacrine cells and strikingly, in the absence of the S3 sublamina, suggesting that LHX9 could be expressed in and be required for the development of a unique, S3-stratifying amacrine subtype cells. Interestingly, our preliminary data show that bNOS expression is significantly down-regulated in the Lhx9-null retina, suggesting a loss of bNOS-subtype of amacrine cells that are known to project in the S3 sublamina. Being a transcription factor with a known function in neuronal subtype development in the central nervous system, LHX9 likely plays a critic role in amacrine subtype specification and offers us a unique opportunity to ultimately elucidate the genetic pathway governing the formation of the S3 sublamina and its associated neural circuitry. In this proposal, we will fully characterize the subtype identity of these LHX9-expressing amacrine subtypes and will identify its circuitry within the retina. Second, we will analyze the retinal defects of Lhx9-null mutation, particularly the effect on amacrine subtype specification, differentiation of these Lhx9-expressing S3 stratifying amacrine cells, and the change in the functional properties and circuitry of the Lhx9-lineage cells. To elucidate the LHX9 regulatory pathway in the S3-stratifying amacrine cells, we will perform RNA-Seq of control and Lhx9-null retinas and use LHX9 ChIP-Seq to screen for downstream target genes of LHX9 and to identify the transcriptional network. Together, these studies will define the role of LHX9 in regulating the formation and neural circuitry of S3 sublamina and elucidate the transcriptional events that occur downstream of LHX9.