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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.

Record Type:	Electronic resources : Monograph/item
Title/Author:	Regulatory Mutation Disrupting Methylsterol Monooxygenase 1 Expression Reveals Role of Cholesterol Genes in Zebrafish Skeletogenesis./
Author:	Anderson, Rebecca.
Published:	Ann Arbor : ProQuest Dissertations & Theses, : 2019,
Description:	139 p.
Notes:	Source: Dissertations Abstracts International, Volume: 81-08, Section: B.
Contained By:	Dissertations Abstracts International81-08B.
Subject:	Developmental biology. -
Online resource:	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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245 1 0 $a Regulatory Mutation Disrupting Methylsterol Monooxygenase 1 Expression Reveals Role of Cholesterol Genes in Zebrafish Skeletogenesis.
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300 $a 139 p.
500 $a Source: Dissertations Abstracts International, Volume: 81-08, Section: B.
500 $a Advisor: Topczewski, Jacek;Mitchell, Brian J.
502 $a Thesis (Ph.D.)--Northwestern University, 2019.
506 $a This item must not be sold to any third party vendors.
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.
590 $a School code: 0163.
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653 $a Cholesterol
653 $a Chondrodysplasia punctata
653 $a lss
653 $a Msmo1
653 $a Skeletogenesis
653 $a Zebrafish
690 $a 0758
710 2 $a Northwestern University. $b Driskill Graduate Training Program in Life Sciences. $3 3282984
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