Defense Date

2019

Document Type

Thesis

Degree Name

Doctor of Philosophy

Department

Integrative Life Sciences

First Advisor

Gregory Walsh

Abstract

The directed migration of neurons is influenced by multiple guidance cues, that may include soluble attractive chemotactic factors and cell-cell contact mediated collective migration. The nature of these neuron-neuron interactions and their integration with chemotaxis remains unclear. Contact inhibition of locomotion (CIL), a process whereby cells undergoing a collision cease their migration towards the colliding cell, has been identified as a driving force behind the collective migration of several cell populations in vivo, but has not been described for neurons in the central nervous system. We have established that Cadherin2 (Cdh2), a cell adhesion molecule, mediates the physical interactions between facial branchiomotor neurons (FBMNs) that promote the collective mode of migration. Using live imaging, we observed transient cell-cell contact between the somas of FBMNs during migration. Following neuron-neuron collisions, we observed two directional outcomes: i) both neurons remain travelling posteriorly, or ii) the neurons migrate in opposite directions (one anterior and one posterior). This latter observation is a hallmark of CIL behavior. These CIL events occur in approximately 50% of soma-soma collisions. Consistent with the repulsive nature of CIL events, live imaging of Tg(isl1:GFP-CAAX)fish show that CIL events are characterized by a collapse of protrusions upon collision. Our data indicate that CIL-based neuron-neuron interactions influence the directionality of FBMN movement and may underlie the collective nature of FBMN migration. To determine whether chemotaxis could influence FBMN directionality after cell-cell collisions, we examined the interplay between Cdh2-mediated collective migration and SDF1a-mediated chemotaxis. We found partial FBMN migration defects under conditions when Cdh2 function is partially inactivated or when the chemokine SDF1a is knocked down. Strikingly, we find an almost complete migration block when both SDF1a is depleted and Cdh2 function is inactivated. These findings suggest that FBMNs integrate multiple inputs arising from cell-cell contact induced polarity changes and SDF1a-mediated chemotaxis to achieve sustained directed migration.

Rights

© The Author

Is Part Of

VCU University Archives

Is Part Of

VCU Theses and Dissertations

Date of Submission

7-28-2019

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