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Temporal specification and bilaterality of human neocortical topographic gene expression.

ABSTRACT: Transcriptional events involved in the development of human cerebral neocortex are poorly understood. Here, we analyzed the temporal dynamics and laterality of gene expression in human and macaque monkey neocortex. We found that interareal differences exhibit a temporal hourglass pattern, dividing the human neocortical development into three major phases. The first phase, corresponding to prenatal development, is characterized by the highest number of differential expressed genes among areas and gradient-like expression patterns, including those that are different between human and macaque. The second, preadolescent phase, is characterized by lesser interareal expression differences and by an increased synchronization of areal transcriptomes. During the third phase, from adolescence onward, differential expression among areas increases again driven predominantly by a subset of areas, without obvious gradient-like patterns. Analyses of left-right gene expression revealed population-level global symmetry throughout the fetal and postnatal time span. Thus, human neocortical topographic gene expression is temporally specified and globally symmetric.

SUBMITTER: Pletikos M

PROVIDER: S-EPMC3931000 | biostudies-literature | 2014 Jan

REPOSITORIES: biostudies-literature

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Temporal specification and bilaterality of human neocortical topographic gene expression.

Pletikos Mihovil M Sousa André M M AM Sedmak Goran G Meyer Kyle A KA Zhu Ying Y Cheng Feng F Li Mingfeng M Kawasawa Yuka Imamura YI Sestan Nenad N

Neuron 20131226 2

Transcriptional events involved in the development of human cerebral neocortex are poorly understood. Here, we analyzed the temporal dynamics and laterality of gene expression in human and macaque monkey neocortex. We found that interareal differences exhibit a temporal hourglass pattern, dividing the human neocortical development into three major phases. The first phase, corresponding to prenatal development, is characterized by the highest number of differential expressed genes among areas and ...[more]

PMID: 24373884

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Project description:PurposeRetinitis pigmentosa (RP) typically results from individual mutations in any one of >70 genes that cause rod photoreceptor cells to degenerate prematurely, eventually resulting in blindness. Gene therapies targeting individual RP genes have shown efficacy at clinical trial; however, these therapies require the surviving photoreceptor cells to be viable and functional, and may be economically feasible for only the more commonly mutated genes. An alternative potential treatment strategy, particularly for late stage disease, may involve stem cell transplants into the photoreceptor layer of the retina. Rod progenitors from postnatal mouse retinas can be transplanted and can form photoreceptors in recipient adult retinas; optimal numbers of transplantable cells are obtained from postnatal day 3-5 (P3-5) retinas. These cells can also be expanded in culture; however, this results in the loss of photoreceptor potential. Gene expression differences between postnatal retinas, cultured retinal progenitor cells (RPCs), and rod photoreceptor precursors were investigated to identify gene expression patterns involved in the specification of rod photoreceptors.MethodsMicroarrays were used to investigate differences in gene expression between cultured RPCs that have lost photoreceptor potential, P1 retinas, and fresh P5 retinas that contain significant numbers of transplantable photoreceptors. Additionally, fluorescence-activated cell sorting (FACS) sorted Rho-eGFP-expressing rod photoreceptor precursors were compared with Rho-eGFP-negative cells from the same P5 retinas. Differential expression was confirmed with quantitative polymerase chain reaction (q-PCR).ResultsAnalysis of the microarray data sets, including the use of t-distributed stochastic neighbor embedding (t-SNE) to identify expression pattern neighbors of key photoreceptor specific genes, resulted in the identification of 636 genes differentially regulated during rod specification. Forty-four of these genes when mutated have previously been found to cause retinal disease. Although gene function in other tissues may be known, the retinal function of approximately 61% of the gene list is as yet undetermined. Many of these genes' promoters contain binding sites for the key photoreceptor transcription factors Crx and Nr2e3; moreover, the genomic clustering of differentially regulated genes appears to be non-random.ConclusionsThis study aids in understanding gene expression differences between rod photoreceptor progenitors versus cultured RPCs that have lost photoreceptor potential. The results provide insights into rod photoreceptor development and should expedite the development of cell-based treatments for RP. Furthermore, the data set includes a large number of retinopathy genes; less-well-characterized genes within this data set are a resource for those seeking to identify novel retinopathy genes in patients with RP (GEO accession: GSE59201).

Dataset Information

Temporal specification and bilaterality of human neocortical topographic gene expression.

Publications

Temporal specification and bilaterality of human neocortical topographic gene expression.

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