Date of Award
Doctor of Philosophy (PhD)
Cell & Molecular Biology
Jeffrey A. Golden
Stewart A. Anderson
During the development of the cortex neurons must migrate from their sites of birth to their final destinations. There are two main types of migration in the developing cortex, the radial migration of pyramidal neurons and the non-radial migration of cortical interneurons. There are limited studies directly comparing these two migration processes, and thus our understanding for perturbations that are selective to either non-radial versus radial migration is limited. Understanding causes of disruption of interneuron migration specifically is clinically relevant due to several interneuron specific developmental diseases. There is a growing body of literature observing a link between interneuron disorders and mitochondrial dysfunction, and thus regulation of mitochondria and their functions are promising targets for identifying selective effects on interneuron development. Mitochondria are organelles serving multiple functions in cells, including energy production, calcium buffering, redox homeostasis, and regulation of cell death. Although mitochondria are known to play essential roles in maintaining neuronal health and function in the adult brain, the importance of mitochondria during neuronal development is poorly understood.
Using in vitro mouse brain explant and slice culture systems, we observed distinct localization patterns of mitochondria between interneurons and pyramidal neurons. Mitochondria in migrating interneurons move cyclically throughout the cell during the migration process while remaining in front of the nucleus in migrating radial neurons. Fluorescence immunohistochemistry confirmed these localization patterns in embryonic mouse brains in vivo.
We then applied pharmacologic tools to disrupt mitochondrial oxidative phosphorylation and discovered that interneuron migration is profoundly sensitive to these disruptions compared to radially migrating pyramidal neurons. This was confirmed by examination of a genetic model of compromised oxidative phosphorylation (Ant1). Interneurons with compromised mitochondrial function exhibit decreased migration, increased changes in direction, increased trailing process length, changes in branching behavior, and shifts in centrosome positioning.
We then utilized a dominant negative form of Miro1, a protein involved in mitochondrial trafficking to alter mitochondrial trafficking behavior. We also observed increased direction changes and reduced ability of interneurons to invade the cortex. However, interneuron migration rate was unaffected. The changes in cell migration behavior suggest that mitochondria play a central role in maintaining interneuron cell polarity to allow for progressive interneuron migration during their long journey.
These data collectively support a model in which mitochondrial perturbations have a selective effect on interneuron migration. This work suggests that neuronal deficits occurring in mitochondrial disorders are not exclusively due to neuronal metabolic insufficiency in postnatal stages, but can also have developmental origins.
Lin-Hendel, Erika G., "Differential Requirements For Mitochondria During Neuronal Migration" (2017). Publicly Accessible Penn Dissertations. 2424.