In both insects and mammals, a relatively small group of neural progenitors gives rise to diverse neural cells which must be made at the right time, place, and abundance to form a functional brain. Neural progenitors sequentially make distinct cell types in an invariant order, and over time they lose potential (or ?competence?) to specify earlier-born cell fates as they acquire competence to generate the later-born fates. Thus, competence is a fundamental property of progenitors that ensures the production of particular cell types at the right developmental stages. How competence transitions are regulated and how they are developmentally timed is largely unknown. We propose to study these mechanisms, which will be highly impactful in our fundamental understanding of brain development and origin of neurodevelopmental disorders. The Drosophila embryo is an ideal system to uncover mechanisms regulating progenitor competence, because of the ability to track single neural lineages over time and the large number of genetic tools available. In the embryonic nerve cord there are ~30 distinct neuroblasts (NBs, neural progenitors), and each generates a unique lineage of neural cells. Cell fate is specified based on birth order, with successive NB divisions sequentially expressing the transcription factors Hunchback (hb), Kruppel, Pou domain protein, and Castor. The neural progeny in turn maintain active transcription of these factors indefinitely. NB competence to specify early-born fate is restricted to a limited time window, and we found the window closes when the hb genomic locus relocates to the nuclear lamina, where it is permanently silenced. We hypothesize that NB competence is regulated through global reorganization of genome architecture, and that synergistic activity of cell-intrinsic and extrinsic factors determines the developmental timing of competence restriction. To study the mechanisms underlying NB competence restriction, we will examine the function of two nuclear factors that we discovered regulate the length of the NB competence window. Further, using new tools we have generated to profile NBs at specific developmental stages, we will explore changes in the epigenetic landscape and global gene-lamina associations of NBs over time. In particular, we will study whether the hb gene's epigenetic status prior to relocation to the nuclear lamina is required to ?prime? the gene for silencing or whether lamina-tethering is sufficient for competence loss. Our model system is ideally suited to address this question, because we have precise information of the hb gene's transcriptional state, subnuclear gene localization, and NB competence at each cell division. Finally, we found that the steroid hormone Ecdysone plays a role in NB competence, and we will examine how this global extrinsic signal regulates the developmental timing of competence restriction. Together, our proposed studies will provide novel insights into the basic mechanisms of neural progenitor competence regulation and how it is coordinated through time and space.

Public Health Relevance

One of the hallmarks of brain development is that neural progenitors make different cell types in a specific order, and over time, they lose potential to make the cell types born early in development as they acquire new potential to make cell types born later. We aim to study the molecular mechanisms underlying progenitor potential and understand what controls the timing with which it changes over development. The proposed project will advance our ability to harness stem cells to replace cells lost due to injury or disease and provide insights into understanding the origin of neurodevelopmental disorders, such as autism and schizophrenia.

National Institute of Health (NIH)
Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD)
Research Project (R01)
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Neurogenesis and Cell Fate Study Section (NCF)
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Henken, Deborah B
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Columbia University (N.Y.)
Schools of Medicine
New York
United States
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