Neural migration : from development to disease / Matthew F. McManus.

Format:

Book

Manuscript

Microformat

Thesis/Dissertation

Author/Creator:

McManus, Matthew F.

Contributor:

Golden, Jeffrey A., 1961- advisor.

University of Pennsylvania.

Language:

English

Subjects (All):

Penn dissertations--Neuroscience.

Neuroscience--Penn dissertations.

Neurosciences.

Academic Dissertations as Topic.

Medical Subjects:

Neurosciences.

Academic Dissertations as Topic.

Local Subjects:

Penn dissertations--Neuroscience.

Neuroscience--Penn dissertations.

Physical Description:

ix, 96 pages : color illustrations ; 29 cm

Production:

2003.

Summary:

Cellular migration is a hallmark of nervous system development. Glial dependent radial cell migration (RCM) has been well studied, while non-radial cell migration (NRCM) has been appreciated only recently and is the primary pathway along which inhibitory interneurons migrate into the cortex. The substrates of NRCM and the role of intracellular components in normal and abnormal NRCM remain largely unknown.

To determine if non-radially migrating cells utilize axons as substrates, we developed an in vitro preparation that involves culturing individual axons, allowing labeled inhibitory interneurons to associate with them and subsequently assaying for migration. We show that cells are able to migrate in a contact dependent manner along axons. By varying substrate axon types (TAG-1 or neurofilament positive) and using migratory cell populations from different developmental periods, we also demonstrate that changes in axonal substrate requirements parallel developmental changes in migrating interneuron phenotypes. We also characterize Slit-1 and Slit-2 as molecules that are inhibitory in NRCM.

Defects in RCM lead to a variety of developmental defects. Lissencephaly is an example of such a disorder in humans, and a mouse model of the disease caused by a mutation in the Lis1 gene has a known RCM defect. We have shown that a defect in inhibitory interneuron NRCM exists in vivo in mutant mice due to slowed NRCM. This defect is both cell autonomous and non-autonomous. We also demonstrate that humans with mutations in LIS1 have less than the normal complement of cortical inhibitory interneurons.

Different axonal substrate requirements in NRCM likely direct different subpopulations of interneurons to the appropriate location. Further, the axon-dependent migration assay can be used to identify and test candidate molecules in NRCM. This will be important in determining the potential causes of human diseases, as we have shown that NRCM defects in inhibitory interneurons likely contribute to the seizure phenotype characteristic of human Lissencephaly. The concept that perturbed NRCM causes pathology is an important contribution to our understanding of human disease.

Notes:

Supervisor: Jeffrey A. Golden.

Thesis (Ph.D. in Neuroscience) -- University of Pennsylvania, 2003.

Includes bibliographical references.

Local Notes:

University Microfilms order no.: 3095921.

OCLC:

244973211