Dataset Information

Dopey2 and Pcdh7 orchestrate the development of embryonic neural stem cells/ progenitors in zebrafish.

ABSTRACT: DOPEY2 has been shown to be associated with Down syndrome and PCDH7 might be involved in Rett syndrome and MECP2 duplication syndrome. The mechanism how both proteins play roles in these syndromes are largely unknown. Here, we show that Dopey2 and Pcdh7 balance the proliferation and differentiation of neural stem cells and progenitors during embryonic neurogenesis to generate proper size and architecture of zebrafish brains. Dopey2 and Pcdh7 mutually restricted expression of each other in zebrafish embryos. Dopey2 was responsible for the proliferation of neural stem cells/progenitors, whereas Pcdh7 was responsible for the differentiation of neural stem cells/progenitors. Both proteins were shown to orchestrate the proper development and arrangement of neural cells in zebrafish embryonic brains. The results provide an insight into mechanisms to understand how the embryonic brain is constituted and how developmental defects occur in the brains of patients with Down syndrome, Rett syndrome, or MECP2 duplication syndrome.

SUBMITTER: Xiao Y

PROVIDER: S-EPMC10014312 | biostudies-literature | 2023 Mar

REPOSITORIES: biostudies-literature

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Dopey2 and Pcdh7 orchestrate the development of embryonic neural stem cells/ progenitors in zebrafish.

Xiao Yue Y Hu Min M Lin Qiyan Q Zhang Ting T Li Siying S Shu Linjuan L Song Xiuli X Xu Xiaoyong X Meng Wentong W Li Xue X Xu Hong H Mo Xianming X

iScience 20230225 3

DOPEY2 has been shown to be associated with Down syndrome and PCDH7 might be involved in Rett syndrome and <i>MECP2</i> duplication syndrome. The mechanism how both proteins play roles in these syndromes are largely unknown. Here, we show that Dopey2 and Pcdh7 balance the proliferation and differentiation of neural stem cells and progenitors during embryonic neurogenesis to generate proper size and architecture of zebrafish brains. Dopey2 and Pcdh7 mutually restricted expression of each other in ...[more]

PMID: 36936789

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Project description:Human embryonic stem cells (hESCs) and neural progenitor (NP) cells are excellent models for recapitulating early neuronal development in vitro, and are key to establishing strategies for the treatment of degenerative disorders. While much effort had been undertaken to analyze transcriptional and epigenetic differences during the transition of hESC to NP, very little work has been performed to understand post-transcriptional changes during neuronal differentiation. Alternative RNA splicing (AS), a major form of post-transcriptional gene regulation, is important in mammalian development and neuronal function. Human ESC, hESC-derived NP, and human central nervous system stem cells were compared using Affymetrix exon arrays. We introduced an outlier detection approach, REAP (Regression-based Exon Array Protocol), to identify 1,737 internal exons that are predicted to undergo AS in NP compared to hESC. Experimental validation of REAP-predicted AS events indicated a threshold-dependent sensitivity ranging from 56% to 69%, at a specificity of 77% to 96%. REAP predictions significantly overlapped sets of alternative events identified using expressed sequence tags and evolutionarily conserved AS events. Our results also reveal that focusing on differentially expressed genes between hESC and NP will overlook 14% of potential AS genes. In addition, we found that REAP predictions are enriched in genes encoding serine/threonine kinase and helicase activities. An example is a REAP-predicted alternative exon in the SLK (serine/threonine kinase 2) gene that is differentially included in hESC, but skipped in NP as well as in other differentiated tissues. Lastly, comparative sequence analysis revealed conserved intronic cis-regulatory elements such as the FOX1/2 binding site GCAUG as being proximal to candidate AS exons, suggesting that FOX1/2 may participate in the regulation of AS in NP and hESC. In summary, a new methodology for exon array analysis was introduced, leading to new insights into the complexity of AS in human embryonic stem cells and their transition to neural stem cells.

Dataset Information

Dopey2 and Pcdh7 orchestrate the development of embryonic neural stem cells/ progenitors in zebrafish.

Publications

Dopey2 and Pcdh7 orchestrate the development of embryonic neural stem cells/ progenitors in zebrafish.

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