Deregulation of Neuro-Developmental Genes and Primary Cilium Cytoskeleton Anomalies in iPSC Retinal Sheets from Human Syndromic Ciliopathies

被引：12

作者：

Barabino, Andrea ^{[1
]}

Flamier, Anthony ^{[1
,8
]}

Hanna, Roy ^{[1
]}

Heon, Elise ^{[2
]}

Freedman, Benjamin S. ^{[3
,4
,5
]}

Bernier, Gilbert ^{[1
,6
,7
]}

机构：

[1] Hop Maison Neuve Rosemont, Stem Cell & Dev Biol Lab, 5415 Boul Assomption, Montreal, PQ H1T 2M4, Canada

[2] Hosp Sick Children, Dept Ophthalmol & Vis Sci, Program Genet & Genome Biol, 555 Univ Av, Toronto, ON M5G 1X8, Canada

[3] Univ Washington, Kidney Res Inst, Div Nephrol, Dept Med,Sch Med, Seattle, WA 98109 USA

[4] Univ Washington, Inst Stem Cell & Regenerat Med, Sch Med, Seattle, WA 98109 USA

[5] Univ Washington, Dept Pathol, Sch Med, Seattle, WA 98109 USA

[6] Univ Montreal, Dept Neurosci, Montreal, PQ H3C 3J7, Canada

[7] Univ Montreal, Dept Ophthalmol, Montreal, PQ H3C 3J7, Canada

[8] MIT, Whitehead Inst Biomed Res, 455 Main St, Cambridge, MA 02142 USA

来源：

STEM CELL REPORTS | 2020年 / 14卷 / 03期

基金：

加拿大自然科学与工程研究理事会;

关键词：

MECKEL-GRUBER; MOUSE MODEL; PROTEIN; CELL; EXPRESSION; CENTRIOLE; INITIATION; MUTATIONS; TRANSPORT; PATHOLOGY;

D O I：

10.1016/j.stemcr.2020.02.005

中图分类号：

Q813 [细胞工程];

学科分类号：

摘要：

Ciliopathies are heterogeneous genetic diseases affecting primary cilium structure and function. Meckel-Gruber (MKS) and Bardet-Biedl (BBS) syndromes are severe ciliopathies characterized by skeletal and neurodevelopment anomalies, including polydactyly, cognitive impairment, and retinal degeneration. We describe the generation and molecular characterization of human induced pluripotent stem cell (iPSC)-derived retinal sheets (RSs) from controls, and MKS (TMEM67) and BBS (BBS10) cases. MKS and BBS RSs displayed significant common alterations in the expression of hundreds of developmental genes and members of the WNT and BMP pathways. Induction of crystallin molecular chaperones was prominent in MKS and BBS RSs suggesting a stress response to misfolded proteins. Unique to MKS photoreceptors was the presence of supernumerary centrioles and cilia, and aggregation of ciliary proteins. Unique to BBS photoreceptors was the accumulation of DNA damage and activation of the mitotic spindle checkpoint. This study reveals how combining cell reprogramming, organogenesis, and next-generation sequencing enables the elucidation of mechanisms involved in human ciliopathies.

引用

页码：357 / 373

页数：17

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