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Cerebral Cortex Advance Access published online on October 27, 2009
Cerebral Cortex, doi:10.1093/cercor/bhp211
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© The Author 2009. Published by Oxford University Press. All rights reserved. For permissions, please e-mail: journals.permissions@oxfordjournals.org

Leading Process Branch Instability in Lis1+/– Nonradially Migrating Interneurons

Pallavi P. Gopal1, Jacqueline C. Simonet2, William Shapiro3 and Jeffrey A. Golden13

1 Neuroscience Graduate Group, University of Pennsylvania School of Medicine, Philadelphia, PA 19104, USA, 2 Cell and Molecular Biology Graduate Group, University of Pennsylvania School of Medicine, Philadelphia, PA 19104, USA, 3 Department of Pathology, Children's Hospital of Philadelphia, University of Pennsylvania School of Medicine, Philadelphia, PA 19104, USA

Address correspondence to Jeffrey A. Golden, Department of Pathology, Children's Hospital of Philadelphia, ARC 516H, University of Pennsylvania School of Medicine, 3400 Civic Center Boulevard, Philadelphia, PA 19104, USA. Email: goldenj{at}mail.med.upenn.edu.

Mammalian forebrain development requires extensive migration, yet the mechanisms through which migrating neurons sense and respond to guidance cues are not well understood. Similar to the axon growth cone, the leading process and branches of neurons may guide migration, but the cytoskeletal events that regulate branching are unknown. We have previously shown that loss of microtubule-associated protein Lis1 reduces branching during migration compared with wild-type neurons. Using time-lapse imaging of Lis1+/– and Lis1+/+ cells migrating from medial ganglionic eminence explant cultures, we show that the branching defect is not due to a failure to initiate branches but a defect in the stabilization of new branches. The leading processes of Lis1+/– neurons have reduced expression of stabilized, acetylated microtubules compared with Lis1+/+ neurons. To determine whether Lis1 modulates branch stability through its role as the noncatalytic β regulatory subunit of platelet-activating factor (PAF) acetylhydrolase 1b, exogenous PAF was applied to wild-type cells. Excess PAF added to wild-type neurons phenocopies the branch instability observed in Lis1+/– neurons, and a PAF antagonist rescues leading process branching in Lis1+/– neurons. These data highlight a role for Lis1, acting through the PAF pathway, in leading process branching and microtubule stabilization.

Key Words: branching • leading process • microtubules • migration • PAFAH1b


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