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Regulatory Mutation Disrupting Methy...

Anderson, Rebecca.

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Regulatory Mutation Disrupting Methylsterol Monooxygenase 1 Expression Reveals Role of Cholesterol Genes in Zebrafish Skeletogenesis.

紀錄類型:	書目-電子資源 : Monograph/item
正題名/作者:	Regulatory Mutation Disrupting Methylsterol Monooxygenase 1 Expression Reveals Role of Cholesterol Genes in Zebrafish Skeletogenesis./
作者:	Anderson, Rebecca.
出版者:	Ann Arbor : ProQuest Dissertations & Theses, : 2019,
面頁冊數:	139 p.
附註:	Source: Dissertations Abstracts International, Volume: 81-08, Section: B.
Contained By:	Dissertations Abstracts International81-08B.
標題:	Developmental biology. -
電子資源:	http://pqdd.sinica.edu.tw/twdaoapp/servlet/advanced?query=22623085
ISBN:	9781392475775

Regulatory Mutation Disrupting Methylsterol Monooxygenase 1 Expression Reveals Role of Cholesterol Genes in Zebrafish Skeletogenesis.
Anderson, Rebecca.

Regulatory Mutation Disrupting Methylsterol Monooxygenase 1 Expression Reveals Role of Cholesterol Genes in Zebrafish Skeletogenesis. - Ann Arbor : ProQuest Dissertations & Theses, 2019 - 139 p.

Source: Dissertations Abstracts International, Volume: 81-08, Section: B.

Thesis (Ph.D.)--Northwestern University, 2019.

This item must not be sold to any third party vendors.

Human disorders of the post-squalene biosynthesis cholesterol pathway frequently result in skeletal abnormalities, yet our understanding of the mechanisms involved is limited. In a forward genetic approach, we characterized a late-onset skeletal mutant, named kolibernu7, which is the result of a cis-acting regulatory mutation leading to loss of methylsterol monooxygenase 1 (msmo1) expression within prehypertrophic chondrocytes. To dissect the effects of cholesterol deprivation from sterol intermediate accumulation, we eliminated the activity of Lanosterol synthase (Lss). Double lssnu60;msmo1nu81 and single lssnu60 mutants survive significantly longer than msmo1nu81 homozygotes. Liver-specific restoration of either Msmo1 or Lss in corresponding mutant backgrounds suppresses larva lethality but results in skeletal abnormalities, with a loss of Msmo1 activity resulting in a more severe patterning defect of a near-complete loss of hypertrophic chondrocytes marked by col10a1 expression. Our analysis suggests that hypertrophic chondrocytes depend on endogenous cholesterol synthesis, and blocking C4 demethylation exacerbates the cholesterol deficiency phenotype. Our findings offer new insight into the genetic control of bone development and provide new zebrafish models for human disorders of the cholesterol pathway.

ISBN: 9781392475775Subjects--Topical Terms:

592588
Developmental biology.
Subjects--Index Terms:

Cholesterol

Regulatory Mutation Disrupting Methylsterol Monooxygenase 1 Expression Reveals Role of Cholesterol Genes in Zebrafish Skeletogenesis.
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520 $a Human disorders of the post-squalene biosynthesis cholesterol pathway frequently result in skeletal abnormalities, yet our understanding of the mechanisms involved is limited. In a forward genetic approach, we characterized a late-onset skeletal mutant, named kolibernu7, which is the result of a cis-acting regulatory mutation leading to loss of methylsterol monooxygenase 1 (msmo1) expression within prehypertrophic chondrocytes. To dissect the effects of cholesterol deprivation from sterol intermediate accumulation, we eliminated the activity of Lanosterol synthase (Lss). Double lssnu60;msmo1nu81 and single lssnu60 mutants survive significantly longer than msmo1nu81 homozygotes. Liver-specific restoration of either Msmo1 or Lss in corresponding mutant backgrounds suppresses larva lethality but results in skeletal abnormalities, with a loss of Msmo1 activity resulting in a more severe patterning defect of a near-complete loss of hypertrophic chondrocytes marked by col10a1 expression. Our analysis suggests that hypertrophic chondrocytes depend on endogenous cholesterol synthesis, and blocking C4 demethylation exacerbates the cholesterol deficiency phenotype. Our findings offer new insight into the genetic control of bone development and provide new zebrafish models for human disorders of the cholesterol pathway.
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