Linking mitochondria to experience-dependent cell proliferation in the developing brain - In the developing brain, neural progenitor cells (NPCs) initially divide symmetrically, make more of
themselves, and expand the size of the NPC pool. Later, their behavior irreversibly changes as they
asymmetrically divide to produce a neuron with each division (the process of neurogenesis). Once neurogenesis
begins, NPCs are committed and they are not able to return to symmetric cell divisions. It is important to the
development of a brain that the change from symmetric to asymmetric cell division does not occur too early,
which limits the number of neurons generated, or too late, which improperly expands the brain. Pockets of NPCs
persist in the brain and continue to divide in adulthood. Limiting neurogenesis in the adult, where the newborn
neurons contribute to learning and memory, may accelerate cognitive decline and inhibit the ability of the brain
to recover from injury. Consequently, mutations, disease or traumas that alter NPC proliferation contribute to the
etiology of many brain disorders. Intrinsic signals like gene expression regulate NPC fate but equally important
are the extrinsic inputs such as brain activity or diffusible signaling molecules. We do not understand the interplay
between these intrinsic and extrinsic inputs and how they come together to control NPCs. Increasing evidence
suggests mitochondria may be central to this process. NPCs rely on aerobic glycolysis, a non-mitochondrial ATP
generating process. Yet, NPCs contain abundant mitochondria with morphological features that change as the
NPC fate changes. The role of mitochondria in NPCs is unclear, but interfering with mitochondrial structure and
function limits the ability of NPC to proliferate. Assessments of cell proliferation have only been conducted thus
far in vitro, where NPCs are divorced from the extrinsic signals of the environmental niche. This is a concern that
my students and I circumvent by studying the NPCs in transparent Xenopus laevis, using in vivo timelapse
confocal microscopy where individual fluorescently-labeled NPCs, their cellular progeny and their labeled
mitochondria can be tracked over days. Will test our hypothesis that mitochondrial biogenesis, mitochondrial
dynamics and the metabolic activity of mitochondria within NPCs are regulated in order to support changes in
the fate of the NPCs. We will analyze and quantify the diversity of mitochondria, their motility and metabolic
potential in the NPCs to determine the features that forecast cell fate (Aim 1). By manipulating mitochondrial
biogenesis in NPCs, we predict that we can force them to leave the symmetrically-dividing population and commit
to neurogenic cell divisions (Aim 2). Finally, sensory experience is a potent regulator cell proliferation, acting
through signaling pathways that also affect mitochondrial function. In Aim 3 we will test whether increasing or
suppressing mitochondrial biogenesis mediates experience-dependent changes in NPC proliferation and
neurogenesis. In this work, students gain expertise in molecular biology techniques and 4D imaging and analysis.
Our results will give insights into the control of cell proliferation in the brain, an important source of plasticity that
may one day be harnessed to treat disease or injury.
