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The role of Lamin B1 in the organization of the nuclear envelope and myelin regulation in development and disease

Nmezi, Bruce (2019) The role of Lamin B1 in the organization of the nuclear envelope and myelin regulation in development and disease. Doctoral Dissertation, University of Pittsburgh. (Unpublished)

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Abstract

The nuclear lamina is a structural meshwork composed of intermediate filament proteins known as lamins that maintains nuclear shape and function. Perturbations of lamins lead to diseases, collectively known as laminopathies, which affect a wide variety of organ systems. One such laminopathy is autosomal dominant leukodystrophy (ADLD), a severe and fatal adult-onset demyelinating laminopathy caused by overexpression of LMNB1, one of the lamin proteins that make up the nuclear lamina. My studies aim to elucidate the role of lamin B1 in the organization of the nuclear envelope, its role in myelin regulation during oligodendrocyte maturation, and to understand how the genomic rearrangements involving LMNB1 cause ADLD. Our results suggest a novel concentric organization model of the nuclear lamina, with lamin B1 facing the inner nuclear membrane while lamins A and C together face the nucleoplasm. Lamin B1’s outward-facing localization maintains nuclear shape by restraining the lamin A/C meshwork from protruding outward. To study lamin B1’s function in mature oligodendrocytes, conditional Lmnb1 knockout mice were used to study behavioral and molecular changes in the central nervous system. Knockout mice did not exhibit any overt behavioral phenotypes or myelination defects, but a careful analysis revealed alterations in the number of myelinating oligodendrocyte populations. We conclude that while mature oligodendrocytes do not require lamin B1 for their proper function, it might be important for the regulation of oligodendrocyte cell number. Array CGH studies revealed that deletions upstream of LMNB1 can also lead to ADLD, while large duplications involving LMNB1 and a significant upstream region do not. Real-time PCR analysis demonstrate much higher LMNB1 expression in white matter than in grey matter and fibroblasts. We propose that an oligodendrocyte-specific silencer element lies upstream of LMNB1, explaining ADLD’s central nervous system exclusivity despite a constitutional LMNB1 duplication. As demyelination and white matter injuries are common in disorders affecting a wide age range – from preterm neonates to young adults and the elderly – researching pathways involved in myelination and ways to reverse it could have a significant impact to public health.


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Details

Item Type: University of Pittsburgh ETD
Status: Unpublished
Creators/Authors:
CreatorsEmailPitt UsernameORCID
Nmezi, Brucenmezib@gmail.combcn6
ETD Committee:
TitleMemberEmail AddressPitt UsernameORCID
Committee ChairPadiath, Quasarqpadiath@pitt.eduqpadiath
Committee MemberDahl, Kriskrisdahl@cmu.edu
Committee MemberNicholls, Robertrobert.nicholls@chp.edu
Committee MemberRoman, Bethromanb@pitt.eduromanb
Committee MemberUrban, Zsolturbanz@pitt.eduurbanz
Date: 26 September 2019
Date Type: Publication
Defense Date: 10 July 2019
Approval Date: 26 September 2019
Submission Date: 16 July 2019
Access Restriction: 1 year -- Restrict access to University of Pittsburgh for a period of 1 year.
Number of Pages: 118
Institution: University of Pittsburgh
Schools and Programs: Graduate School of Public Health > Human Genetics
Degree: PhD - Doctor of Philosophy
Thesis Type: Doctoral Dissertation
Refereed: Yes
Uncontrolled Keywords: Lamin, Myelin, Oligodendrocyte, ADLD, Leukodystrophy, Nucleus
Date Deposited: 26 Sep 2019 16:45
Last Modified: 27 Sep 2019 18:11
URI: http://d-scholarship.pitt.edu/id/eprint/37146

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