Studying the role of semaphorins in axon guidance using a dominant negative neuropilin-1 receptor / Michael J. Renzi.

Format:

Book

Manuscript

Microformat

Thesis/Dissertation

Author/Creator:

Renzi, Michael J.

Contributor:

Raper, Jonathan A., 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, 168 pages : illustrations (some color) ; 29 cm

Production:

1999.

Summary:

The semaphorin family contains both secreted and transmembrane proteins, several of which are thought to be involved in axon guidance. The class 3 secreted semaphorin, SEMA-3A, repel the growth cones of specific neurons. SEMA-3A signaling is mediated by a receptor complex consisting of Neuropilin-1 and Plexins. The purpose of this dissertation is to define the role that neuropilin-1 plays in SEMA-3A signaling. SEMA-3A contains three structural domains: the family signature semaphorin domain, a single C-type Immunoglobulin (Ig) domain, and a C-terminal basic domain. The extra cellular domain of neuropilin-1 contains 5 distinct sub-domains, the a1 and a2 domains, the b1 and b2 domains, and the C-domain. I set out to: (1) define the regions of neuropilin-1 that bind SEMA-3A, (2) determine if a dominant negative neuropilin-1 could be identified, and (3) determine if axon trajectories in vivo could be perturbed by blocking semaphorin function with a dnNP-1. The findings are: (1) SEMA-3A binds to two domains on the extra cellular region of neuropilin-1. One site, located in the b1/b2 domain, binds the Ig-basic tail of SEMA-3A and is responsible for the majority of SEMA-3A binding to neuropilin-1. A second site in the C-domain binds the semaphorin domain of SEMA-3A weakly. (2) The over expression of a specific neuropilin-1 receptor in which the C-domain has been deleted blocks the response of primary sympathetic neurons to specific semaphorins. Dominant negative neuropilin-1 (dnNP- 1) can block the collapse of growth cones from cultured sympathetic neurons induced by SEMA-3A and SEMA-3C, but not collapse induced by SEMA-3F. (3) dnNP-l expressing olfactory sensory axons are more likely to overshoot their target area and enter the CNS than normal axons. Olfactory axons extend from the olfactory epithelium to the rostral-most margin of the telencephalon early during development while the distance is small. However, their ultimate target, the olfactory bulb, has not differentiated when they first arrive. For several days olfactory axons accumulate just outside the CNS while the bulb differentiates and matures. My results suggest that SEMA-3A expressed in the outermost layers of the telencephalon helps to prevent the premature entry of olfactory axons into their target, before it is ready to receive them.

Notes:

Supervisor: Jonathan A. Raper.

Thesis (Ph.D. in Neuroscience) -- University of Pennsylvania, 1999.

Includes bibliographical references.

Local Notes:

University Microfilms order no.: 99-53586.

OCLC:

187484027