Minoree Kohwi, PhD

The brain’s complexity is apparent from the incredible diversity in its cell types. To form the functional circuitry necessary to achieve sophisticated cognitive and motor functions, neural progenitors must make each type of neural cell at the right place and time and also in the correct proportions. The major goal of my lab is to understand the origin of this cellular diversity in the brain and the logic by which it is generated in such a highly organized manner.

A relatively small pool of neural progenitors generates diverse cell types sequentially by responding to changes in cell intrinsic and extrinsic signals. Over time, they lose the ability, or “competence,” to make cell types born at earlier stages and gain competence to make cell types born at later stages. How competence is regulated during development is poorly understood, but has important implications in our basic understanding of brain development, origin of neurodevelopmental disorders, and how we can harness stem cells for brain repair.

The Drosophila Neuroblast system

The Drosophila embryo provides an ideal model to study neural progenitor competence in vivo: there are only ~30 neuroblasts, the fly neural progenitors, in the embryonic nerve cord, and each gives rise to a unique lineage of neurons and glia in an invariant birth order. One of the amazing features of neuroblasts is that each neuroblast and its progeny can be individually identified and tracked over time in vivo. This allows us to reproducibly find the same single progenitor between animals and across development. Critically, the set of transcription factors that specify fate of the neural progeny based on birth order, called “temporal identity factors,” is known and can be exploited to test the neuroblasts’ competence to produce each type of neuron over development.

Mechansisms of neuroblast competence restriction

Using a combination of genetics and DNA FISH (Fluorescence in situ hybridization), we recently discovered that neuroblasts undergo a developmentally-timed reorganization of their genome that physically relocates genes within the nucleus (Kohwi et al., Cell 2013). Genes harbor specific positions relative to various functional compartments within nuclei that can affect whether they can be turned on or off. We discovered that such gene repositioning occurs in neuroblasts in a highly regulated manner, and consequently, determines whether a specific neural cell type can be made at a specific developmental stage. Thus, this restructuring of nuclear architecture appears to regulate the neuroblasts’ competence state (Kohwi and Doe, Nature Rev Neurosci 2013). Current projects focus on understanding how the timing of genome reorganization in neuroblasts is controlled, investigating how the reorganization affects neuroblast output, and translating our findings in the fruit fly to the mouse model system.

(photo credit: Barbara Alper/Columbia University)