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Elucidating the role of SDF1 signaling during cortical interneuron migration / Daniel E. Lysko.
LIBRA R001 2012 .L994
Available from offsite location
- Format:
- Book
- Manuscript
- Thesis/Dissertation
- Author/Creator:
- Lysko, Daniel E.
- Language:
- English
- Subjects (All):
- Penn dissertations--Cell and molecular biology.
- Cell and molecular biology--Penn dissertations.
- Local Subjects:
- Penn dissertations--Cell and molecular biology.
- Cell and molecular biology--Penn dissertations.
- Physical Description:
- ix, 108 pages : color illustrations ; 29 cm
- Production:
- 2012.
- Summary:
- Cell migration is required for normal embryonic development, yet how cells navigate complex paths while integrating multiple guidance cues remains poorly understood. During brain development, interneurons migrate from the ventral ganglionic eminence to the cerebral cortex within several migratory streams. They must exit these streams to invade the cortical plate. While the chemokine stromal cell-derived factor-1 (SDF1) is required for normal interneuron stream migration and cortical plate invasion, the mechanism of SDF1 control of interneuron cortical plate invasion was unknown. Using an in vitro mouse explant system we find that SDF1 reduces interneuron branching and establish the importance of interneuron branching in controlling cortical plate invasion. Blocking SDF1 signaling, or increasing branching frequency, results in stream exit and cortical plate invasion in mouse brain slices. These data support a novel model to understand how migrating interneurons switch from stream migration to invade the cortical plate in which reducing SDF1 signaling increases leading process branching and slows the migration rate, permitting migrating interneurons to sense cortically directed guidance cues. We have also mechanistically linked SDF1's modulation of leading process branching behavior to a dual regulation of both actin and microtubule organization. We find SDF1 consolidates actin at the leading process tip by activating calpain protease and increasing proteolysis of branched-actin-supporting cortactin. Additionally, SDF1 stabilizes the microtubule array near the tip of the leading process by activating the microtubule-associated protein doublecortin (DCX). This allows DCX to bundle microtubules and stabilize the microtubule array within the leading process tip, reducing branching. These data provide mechanistic insight into the regulation of interneuron leading process dynamics during neuronal migration in mice and provides insight into how DCX, a known human neuronal migration disorder gene, participates in this process.
- Notes:
- Adviser: Jeffrey A. Golden.
- Thesis (Ph.D. in Cell and Molecular Biology) -- University of Pennsylvania, 2012.
- Includes bibliographical references.
- OCLC:
- 829426832
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