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Determining the regulation and requirements of the three Aurora kinases in mammalian female meiosis

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Title
Determining the regulation and requirements of the three Aurora kinases in mammalian female meiosis
Name (type = personal)
NamePart (type = family)
Legeza Nguyen
NamePart (type = given)
Alexandra
NamePart (type = date)
1988-
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Alexandra Legeza Nguyen
Role
RoleTerm (authority = RULIB)
author
Name (type = personal)
NamePart (type = family)
Mckim
NamePart (type = given)
Kim
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Kim Mckim
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Advisory Committee
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chair
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Schindler
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Karen
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Karen Schindler
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Advisory Committee
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internal member
Name (type = personal)
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Steward
NamePart (type = given)
Ruth
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Ruth Steward
Affiliation
Advisory Committee
Role
RoleTerm (authority = RULIB)
internal member
Name (type = personal)
NamePart (type = family)
Singson
NamePart (type = given)
Andrew
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Andrew Singson
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Advisory Committee
Role
RoleTerm (authority = RULIB)
internal member
Name (type = personal)
NamePart (type = family)
Jordon
NamePart (type = given)
Phillip
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Phillip Jordon
Affiliation
Advisory Committee
Role
RoleTerm (authority = RULIB)
outside member
Name (type = corporate)
NamePart
Rutgers University
Role
RoleTerm (authority = RULIB)
degree grantor
Name (type = corporate)
NamePart
School of Graduate Studies
Role
RoleTerm (authority = RULIB)
school
TypeOfResource
Text
Genre (authority = marcgt)
theses
OriginInfo
DateCreated (qualifier = exact)
2018
DateOther (type = degree); (qualifier = exact)
2018-05
CopyrightDate (encoding = w3cdtf); (qualifier = exact)
2018
Place
PlaceTerm (type = code)
xx
Language
LanguageTerm (authority = ISO639-2b); (type = code)
eng
Abstract (type = abstract)
Infertility is a condition that impacts 1 in 6 couples worldwide and is defined as the inability to get pregnant, or stay pregnant, after 1 year of trying to conceive. The causes of infertility are vast, and can stem from either the paternal and maternal side or a combination of the two. One common source of infertility is the presence of an abnormal number of chromosomes (aneuploidy) in the developing egg or sperm. Aneuploidies are frequently incompatible with life, and in humans are the major genetic contributor to miscarriage, infertility, developmental disabilities, and failure of in vitro fertilization. While rare in most organisms, humans are particularly prone to chromosomal abnormalities, with 10–30% of fertilized eggs being aneuploid, accounting for nearly one third of miscarriages. This is in stark contrast to only 1-2% of sperm being aneuploid. Aneuploidy in eggs most often arises due to errors in the first meiotic division, accounting for greater than 56% of all occurrences in both male and female meiosis. The Aurora kinases are a family of serine/threonine kinases critical to regulating chromosome segregation and preventing aneuploidy in both mitosis and meiosis. While the functions of these proteins in mitosis are well understood, their function, regulation, and localization in meiosis remains unclear. Here we sought to understand the distinct functions of the three Aurora kinases expressed in female meiosis; Aurora A, Aurora B, and Aurora C. We show that Aurora C localization is regulated via the phosphorylation of Histone 3 at Threonine 3 by Haspin kinase, and this localization is imperative for the correction of aberrant kinetochore-microtubule attachments and mitigating chromatid condensation. Utilizing a meiosis specific Cre-lox system we show for the first time the requirement for Aurora kinase B in mouse oocytes and a specific function in regulating meiotic cohesion. Next we discover the presence of a negative regulatory network among the Aurora kinases, with Aurora C uniquely required to restrict Aurora A to spindle poles while Aurora B is required to restrict Aurora C activity. Failure for any of these kinases to function properly can lead to meiotic arrest, small spindle structures, chromosomal alignment defects, the premature separation of sister chromatids, and ultimately meiotic aneuploidy. Finally, we identified the presence of a human variant in the Aurora kinases that may be protective of gamete euploidy. Understanding how the Aurora kinases regulate meiosis is critical to our understanding of this unique cell cycle and correspondingly, how errors in meiosis I can lead to aneuploidy in eggs. The information discovered in this thesis work provides insight into the basic machinery that controls meiosis and more importantly will pave the way for the development of appropriate diagnostics and interventions to help women achieve pregnancy with egg cells containing the correct number of chromosomes.
Subject (authority = RUETD)
Topic
Cell and Developmental Biology
RelatedItem (type = host)
TitleInfo
Title
Rutgers University Electronic Theses and Dissertations
Identifier (type = RULIB)
ETD
Identifier
ETD_8715
PhysicalDescription
Form (authority = gmd)
electronic resource
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application/pdf
InternetMediaType
text/xml
Extent
1 online resource (xv, 214 p. : ill.)
Note (type = degree)
Ph.D.
Note (type = bibliography)
Includes bibliographical references
Subject (authority = ETD-LCSH)
Topic
Meiosis
Note (type = statement of responsibility)
by Alexandra Legeza Nguyen
RelatedItem (type = host)
TitleInfo
Title
School of Graduate Studies Electronic Theses and Dissertations
Identifier (type = local)
rucore10001600001
Location
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NjNbRU
Identifier (type = doi)
doi:10.7282/T3RN3C96
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Rights

RightsDeclaration (ID = rulibRdec0006)
The author owns the copyright to this work.
RightsHolder (type = personal)
Name
FamilyName
Legeza Nguyen
GivenName
Alexandra
Role
Copyright Holder
RightsEvent
Type
Permission or license
DateTime (encoding = w3cdtf); (qualifier = exact); (point = start)
2018-03-26 10:57:52
AssociatedEntity
Name
Alexandra Legeza Nguyen
Role
Copyright holder
Affiliation
Rutgers University. School of Graduate Studies
AssociatedObject
Type
License
Name
Author Agreement License
Detail
I hereby grant to the Rutgers University Libraries and to my school the non-exclusive right to archive, reproduce and distribute my thesis or dissertation, in whole or in part, and/or my abstract, in whole or in part, in and from an electronic format, subject to the release date subsequently stipulated in this submittal form and approved by my school. I represent and stipulate that the thesis or dissertation and its abstract are my original work, that they do not infringe or violate any rights of others, and that I make these grants as the sole owner of the rights to my thesis or dissertation and its abstract. I represent that I have obtained written permissions, when necessary, from the owner(s) of each third party copyrighted matter to be included in my thesis or dissertation and will supply copies of such upon request by my school. I acknowledge that RU ETD and my school will not distribute my thesis or dissertation or its abstract if, in their reasonable judgment, they believe all such rights have not been secured. I acknowledge that I retain ownership rights to the copyright of my work. I also retain the right to use all or part of this thesis or dissertation in future works, such as articles or books.
RightsEvent
DateTime (encoding = w3cdtf); (qualifier = exact); (point = start)
2018-05-31
DateTime (encoding = w3cdtf); (qualifier = exact); (point = end)
2018-11-30
Type
Embargo
Detail
Access to this PDF has been restricted at the author's request. It will be publicly available after November 30th, 2018.
Copyright
Status
Copyright protected
Availability
Status
Open
Reason
Permission or license
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2018-04-12T14:45:13
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