We are investigating how the central nervous system (CNS) is assembled during embryonic development. This is has several potential human health benefits relevant to the NIH mission. First, the treatment of many neurological disorders would benefit from a method for generating specific types of neurons from the patient's own induced pluripotent stem (IPS) cells. Second, many psychiatric disorders arise in part from developmental defects. Generating therapeutic tools to treat these types of disorders will require a detailed understanding of how each neuronal subtype is normally formed. We have been investigating this question in the model organism Drosophila, which has been profoundly important for discovering mechanisms of neurogenesis relevant in mammals. Much is currently known about how neural progenitors acquire their spatial identity (e.g. forebrain vs. hindbrain) but we still know very little about how they sequentially produce different cell types. We previously identified a series of transcription factors that specify temporal identity within the Drosophila nervous system. Here we focus on three related questions in embryonic progenitors (Aims 1-3) and conclude with the first analysis of temporal identity in a newly discovered Drosophila post- embryonic neural progenitor that shares features with the primate outer ventricular zone progenitor (Aim 4).
In Aim 1, we will determine whether the Hunchback transcription factor acts transiently in progenitors or continuously in post-mitotic neurons to specify "first-born" temporal identity. Because the mammalian Hunchback ortholog Ikaros has a similar role in specifying early-born retinal ganglion cell fates, this aim has the potential to hep design therapeutic treatments to replace a cell type essential for human vision.
In Aim 2, we follow up on results from the previous funding period showing that neural progenitors lose competence over time to form early-born neuron subtypes in response to a pulse of Hunchback expression. We will determine the mechanism of "progressive loss of competence" in these progenitors, aided by the identification of a nuclear protein whose expression mimics the competence window, and whose prolonged expression can extend the competence window.
In Aim 3, we initiate work on a new "Type II" neural stem cell that we and others recently discovered. Each brain lobe contains 8 type II neuroblasts that divide asymmetrically to produce a series of "intermediate neural progenitors (INPs) that each also divide asymmetrically to make a sequence of 10-12 neurons. We will characterize the relationship between neuroblast or INP birthorder and the production of distinct neural subtypes. We have recently identified transcription factors expressed in sequentially in INPs, and we will determine if they specify temporal identity in these sublineages.
The proposed project is relevant to public health because understanding how spatial and temporal cues are integrated by single progenitors to generate unique neuronal subtypes will help guide stem cell therapy for replacing neurons lost to traumatic brain injury (TBI), stroke, disease, or age-related degeneration. Thus, the proposed research is relevant to NIH's mission to reduce the burden to society arising from prevalent environmental and genetic brain disorders.
|Kohwi, Minoree; Lupton, Joshua R; Lai, Sen-Lin et al. (2013) Developmentally regulated subnuclear genome reorganization restricts neural progenitor competence in Drosophila. Cell 152:97-108|
|Bayraktar, Omer Ali; Doe, Chris Q (2013) Combinatorial temporal patterning in progenitors expands neural diversity. Nature 498:449-55|
|Carney, Travis D; Miller, Michael R; Robinson, Kristin J et al. (2012) Functional genomics identifies neural stem cell sub-type expression profiles and genes regulating neuroblast homeostasis. Dev Biol 361:137-46|
|Hirono, Keiko; Margolis, Jonathan S; Posakony, James W et al. (2012) Identification of hunchback cis-regulatory DNA conferring temporal expression in neuroblasts and neurons. Gene Expr Patterns 12:11-7|
|Kohwi, Minoree; Hiebert, Laurel S; Doe, Chris Q (2011) The pipsqueak-domain proteins Distal antenna and Distal antenna-related restrict Hunchback neuroblast expression and early-born neuronal identity. Development 138:1727-35|
|Tran, Khoa D; Miller, Michael R; Doe, Chris Q (2010) Recombineering Hunchback identifies two conserved domains required to maintain neuroblast competence and specify early-born neuronal identity. Development 137:1421-30|
|Miller, Michael R; Robinson, Kristin J; Cleary, Michael D et al. (2009) TU-tagging: cell type-specific RNA isolation from intact complex tissues. Nat Methods 6:439-41|
|Doe, Chris Q (2008) Neural stem cells: balancing self-renewal with differentiation. Development 135:1575-87|
|Chabu, Chiswili; Doe, Chris Q (2008) Dap160/intersectin binds and activates aPKC to regulate cell polarity and cell cycle progression. Development 135:2739-46|
|Tran, Khoa D; Doe, Chris Q (2008) Pdm and Castor close successive temporal identity windows in the NB3-1 lineage. Development 135:3491-9|
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