Brain function is based upon the precise connectivity of a large number of neurons. Connectivity in turn depends in large part on the genetically determined wiring properties of neurons, including their neurite projection, branching, and placement of synaptic contacts with specific partners. To understand and manipulate brain circuits one needs a detailed knowledge of how the genes expressed in a developing neuron control the wiring properties of this cell. For genetic studies, Drosophila offers many advantages, in that virtually every gene can be targeted for knock-out or activation in a cell type selective manner. More importantly in the context of studying neuronal circuitry, the Drosophila brain is composed of a manageable number of stereotyped neuronal lineages, groups of neurons descended from individual stem cells (neuroblasts) born in the embryo. During the course of its proliferation, each neuroblast expresses characteristic sets of genes (transcription factors) which are thought to specify the wiring properties of the neurons born from that particular neuroblast during a particular time interval. These neurons form a so called sublineage. To learn about the genetic control of brain circuitry we and others have taken the approach to document the structural properties of lineages and sublineages, and correlate them to the dynamic pattern of gene expression in the neuroblast. During the previous funding period we have generated detailed maps and 3D models of all lineages constituting the adult and larval brain. We here propose three aims that continue and extend this work. First, we will reconstruct the connectivity of a subset of larval brain lineages and their sublineages that form a particular, well characterized circuit. This reconstruction will be done at a so far unparalleled level of resolution, using a series of several thousand contiguous electron microscopic sections in conjunction with a specially developed software package that allows us to assign all synapses to specific neurons and their lineages. Secondly, we will link the structurally defined lineages mapped in the larval brain with the neuroblasts of the embryo, using a technique that systematically labels all transcription factors expressed in neuroblasts and then follows the expression of these genes from neuroblast to lineage. Thirdly, we will screen for and genetically characterize genes that play a role in directing lineages to their proper place in a circuit.

Public Health Relevance

Brain function in health and disease is based upon the precise connectivity of a large number of neurons, which in turn are controlled by the patterns of genes expressed in the stem cells that produce neurons. Our studies show that the Drosophila brain is composed of stereotypic groups (lineages) of neurons in which gene expression can be closely correlated with neuronal structure and connectivity. By analyzing the precise role particular genes play in shaping the connections between Drosophila neurons, our research contributes genetic data and concepts which are important to understand and manipulate the mechanisms that control the circuits formed by nerve cells of the human brain.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS054814-14
Application #
9729839
Study Section
Neurogenesis and Cell Fate Study Section (NCF)
Program Officer
Gnadt, James W
Project Start
2006-02-01
Project End
2020-06-30
Budget Start
2019-07-01
Budget End
2020-06-30
Support Year
14
Fiscal Year
2019
Total Cost
Indirect Cost
Name
University of California Los Angeles
Department
Biochemistry
Type
Schools of Arts and Sciences
DUNS #
092530369
City
Los Angeles
State
CA
Country
United States
Zip Code
90095
Hartenstein, Volker; Omoto, Jaison J; Ngo, Kathy T et al. (2018) Structure and development of the subesophageal zone of the Drosophila brain. I. Segmental architecture, compartmentalization, and lineage anatomy. J Comp Neurol 526:6-32
Deng, Hansong; Takashima, Shigeo; Paul, Manash et al. (2018) Mitochondrial dynamics regulates Drosophila intestinal stem cell differentiation. Cell Death Discov 4:17
Hartenstein, Volker; Giangrande, Angela (2018) Connecting the nervous and the immune systems in evolution. Commun Biol 1:64
De Miguel-Bonet, Maria Del Mar; Ahad, Sally; Hartenstein, Volker (2018) Role of neoblasts in the patterned postembryonic growth of the platyhelminth Macrostomum lignano. Neurogenesis (Austin) 5:e14699441-e14699449
Kendroud, Sarah; Bohra, Ali A; Kuert, Philipp A et al. (2018) Structure and development of the subesophageal zone of the Drosophila brain. II. Sensory compartments. J Comp Neurol 526:33-58
Boyan, George; Liu, Yu; Khalsa, Sat Kartar et al. (2017) A conserved plan for wiring up the fan-shaped body in the grasshopper and Drosophila. Dev Genes Evol 227:253-269
Hartenstein, Volker; Takashima, Shigeo; Hartenstein, Parvana et al. (2017) bHLH proneural genes as cell fate determinants of entero-endocrine cells, an evolutionarily conserved lineage sharing a common root with sensory neurons. Dev Biol 431:36-47
Ngo, Kathy T; Andrade, Ingrid; Hartenstein, Volker (2017) Spatio-temporal pattern of neuronal differentiation in the Drosophila visual system: A user's guide to the dynamic morphology of the developing optic lobe. Dev Biol 428:1-24
Hartenstein, Volker; Cruz, Louie; Lovick, Jennifer K et al. (2017) Developmental analysis of the dopamine-containing neurons of the Drosophila brain. J Comp Neurol 525:363-379
Omoto, Jaison J; Lovick, Jennifer K; Hartenstein, Volker (2016) Origins of glial cell populations in the insect nervous system. Curr Opin Insect Sci 18:96-104

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