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一种表型挽救方法鉴定出 DiGeorge 综合征小鼠模型中的谱系区域化缺陷。

A phenotypic rescue approach identifies lineage regionalization defects in a mouse model of DiGeorge syndrome.

机构信息

Institute of Genetics and Biophysics, National Research Council (CNR), Naples 80131, Italy.

Istituto di Ricerca e Cura a Carattere Scientifico (IRCCS) SYNLAB SDN, Via Gianturco 113, 80143 Naples, Italy.

出版信息

Dis Model Mech. 2022 Sep 1;15(9). doi: 10.1242/dmm.049415. Epub 2022 Sep 27.

DOI:10.1242/dmm.049415
PMID:35946435
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC9555768/
Abstract

TBX1 is a key regulator of pharyngeal apparatus (PhAp) development. Vitamin B12 (vB12) treatment partially rescues aortic arch patterning defects of Tbx1+/- embryos. Here, we show that it also improves cardiac outflow tract septation and branchiomeric muscle anomalies of Tbx1 hypomorphic mutants. At the molecular level, in vivo vB12 treatment enabled us to identify genes that were dysregulated by Tbx1 haploinsufficiency and rescued by treatment. We found that SNAI2, also known as SLUG, encoded by the rescued gene Snai2, identified a population of mesodermal cells that was partially overlapping with, but distinct from, ISL1+ and TBX1+ populations. In addition, SNAI2+ cells were mislocalized and had a greater tendency to aggregate in Tbx1+/- and Tbx1-/- embryos, and vB12 treatment restored cellular distribution. Adjacent neural crest-derived mesenchymal cells, which do not express TBX1, were also affected, showing enhanced segregation from cardiopharyngeal mesodermal cells. We propose that TBX1 regulates cell distribution in the core mesoderm and the arrangement of multiple lineages within the PhAp.

摘要

TBX1 是咽弓（PhAp）发育的关键调节因子。维生素 B12（vB12）治疗部分挽救了 Tbx1+/-胚胎的主动脉弓模式缺陷。在这里，我们表明它还改善了 Tbx1 功能不全突变体的心脏流出道分隔和鳃弓肌异常。在分子水平上，体内 vB12 处理使我们能够鉴定出 Tbx1 杂合不足调节和治疗挽救的基因。我们发现 SNAI2，也称为 SLUG，由被拯救基因 Snai2 编码，鉴定了一群中胚层细胞，该群与 ISL1+和 TBX1+群体部分重叠，但又不同。此外，SNAI2+细胞定位错误，并且在 Tbx1+/-和 Tbx1-/-胚胎中更倾向于聚集，而 vB12 处理恢复了细胞分布。相邻的神经嵴衍生的间充质细胞也受到影响，表现出与心咽中胚层细胞的分离增强。我们提出 TBX1 调节核心中胚层中的细胞分布和咽弓内多个谱系的排列。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/8f48/9555768/4296b1cfdefb/dmm-15-049415-g12.jpg
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https://cdn.ncbi.nlm.nih.gov/pmc/blobs/8f48/9555768/b7146895cc41/dmm-15-049415-g8.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/8f48/9555768/dd68ce039b51/dmm-15-049415-g9.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/8f48/9555768/d4d2dc83a7d3/dmm-15-049415-g10.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/8f48/9555768/f7a27147cb76/dmm-15-049415-g11.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/8f48/9555768/4296b1cfdefb/dmm-15-049415-g12.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/8f48/9555768/42438f0c1ec8/dmm-15-049415-g1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/8f48/9555768/69f2c69015c1/dmm-15-049415-g2.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/8f48/9555768/d0c83202637b/dmm-15-049415-g3.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/8f48/9555768/8ff677eccc78/dmm-15-049415-g4.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/8f48/9555768/61f1aaa747be/dmm-15-049415-g5.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/8f48/9555768/dc4f1313180a/dmm-15-049415-g6.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/8f48/9555768/3ada3162ef62/dmm-15-049415-g7.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/8f48/9555768/b7146895cc41/dmm-15-049415-g8.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/8f48/9555768/dd68ce039b51/dmm-15-049415-g9.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/8f48/9555768/d4d2dc83a7d3/dmm-15-049415-g10.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/8f48/9555768/f7a27147cb76/dmm-15-049415-g11.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/8f48/9555768/4296b1cfdefb/dmm-15-049415-g12.jpg

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Pharyngeal pouches provide a niche microenvironment for arch artery progenitor specification.咽囊为动脉弓祖细胞的特化提供了小生境微环境。
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Cell-Extracellular Matrix Interactions Play Multiple Essential Roles in Aortic Arch Development.
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Cardiopharyngeal mesoderm origins of musculoskeletal and connective tissues in the mammalian pharynx.心脏咽中胚层起源于哺乳动物咽的骨骼肌和结缔组织。
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