Aneuploidy is the state of having an abnormal number of chromosomes in the genome. Although aneuploidy is often associated with diseases such as cancer and neural degeneration, recent studies have also demonstrated aneuploidy to be a large-effect mutation that could produce dramatic phenotypic variation and enable cells to rapidly adapt to environmental stress. Intriguingly, frequent aneuploidy has been reported to associate with certain normal somatic cells, such as liver hepatocytes and neurons and neural stem cells. The goal of this R21 study is to explore the idea that aneuploidy may be a genetic mechanism contributing to behavioral diversity of neurons. Specifically, we will use in vitro and ex vivo culture and differentiation of mouse neural stem cells (NSCs) as the experimental model to gain a first insight into how aneuploidy impacts the neuronal cell growth and differentiation and what might be the underlying mechanism. We will also investigate, in light of recent studies in unicellular organisms, whether neuronal aneuploidy may be induced by stress and/or provide phenotypic variation that enable evolutionary adaptation to stress conditions encountered by brain cells. Supporting the proposed experiments, we have developed an effective pipeline for the generation and isolation of aneuploid NSCs with homogeneous or heterogeneous karyotypes and established several methods for quantifying chromosome number and karyotyping of single or populations of cells. We have also established in our lab the methods for in vitro and ex vivo differentiation of NSCs. Our proposed study has the potential to shed light on the possible genetic mechanisms underlying neuronal complexity and the general impact of aneuploidy on the development and physiology of differentiated mammalian cells. The knowledge gained could advance the understanding of pathogenesis of brain disorders and other types of diseases due to chromosome numerical abnormalities.

Public Health Relevance

This project explores how alterations in chromosome copy numbers, or aneuploidy, affect the function and development of brain cells. It has the potential to reveal a novel mechanism by which cells of diverse functions and behaviors may be produced in the brain, and whether aneuploidy may also be a linkage between neuronal cells adapting to environmental stress and the development of neural degenerative diseases.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Exploratory/Developmental Grants (R21)
Project #
7R21NS087485-02
Application #
9101062
Study Section
Nuclear and Cytoplasmic Structure/Function and Dynamics Study Section (NCSD)
Program Officer
Lavaute, Timothy M
Project Start
2015-08-01
Project End
2016-07-31
Budget Start
2015-08-01
Budget End
2016-07-31
Support Year
2
Fiscal Year
2015
Total Cost
$202,500
Indirect Cost
$77,500
Name
Johns Hopkins University
Department
Anatomy/Cell Biology
Type
Schools of Medicine
DUNS #
001910777
City
Baltimore
State
MD
Country
United States
Zip Code
21205
Potapova, Tamara A; Unruh, Jay R; Box, Andrew C et al. (2015) Karyotyping human and mouse cells using probes from single-sorted chromosomes and open source software. Biotechniques 59:335-6, 338, 340-2 passim