Astrocytes are the major cell type in the human brain and in recent years have emerged as critical regulators of neural circuit development, function, plasticity, and maintenance. An array of devastating neurological conditions result from astrocyte dysfunction including childhood periventricular leukomalacia, amyotrophic lateral sclerosis, and gliomas, one of the most deadly forms of cancer. Despite their fundamental importance in brain development and health, we know surprisingly little at the molecular level regarding astrocyte specification, growth, and functional interactions with neurons or synapses. We have recently made the exciting discovery that the Drosophila embryonic, larval, and adult nervous system houses a novel cell type that appears strikingly similar to mammalian astrocytes by morphological, functional, and molecular criteria. For example, fly astrocytes are only found in synapse-rich regions of the brain where they acquire a highly branched morphology, they associate closely with synapses, tile with one another to occupy unique spatial domains in the CNS, and express neurotransmitter transporters and metabolizing enzymes (e.g. EAATs, glutamine synthetase, and GABA transporters). This proposal aims to use the powerful array of molecular-genetic tools available in Drosophila, along with a number of astrocyte-specific tools we have generated, to explore fundamental questions in astrocyte biology. In this project we will (Aim1) characterize astrocyte morphology, synaptic association, polarity, and the cell-cell interactions that sculpt astrocyte architecture;
(Aim 2) determine the role of the Heartless FGF receptor signaling pathway in promoting astrocyte morphogenesis and synaptic association, and (Aim 3) perform the first forward genetic screen for mutants affecting astrocyte development. We expect our work will provide exciting new insights into the molecular and cellular mechanisms regulating astrocyte development and growth control in vivo, and be highly informative in forwarding our understanding astrocyte development and dysfunction in humans.

Public Health Relevance

Astrocytes are the most abundant cell type in the human brain and have emerged as key regulators of brain development, function, and maintenance. Astrocyte dysfunction results in devastating neurological conditions including periventricular leukomalacia, amyotrophic lateral sclerosis, and gliomas, one of the most deadly forms of cancer. Our work will provide fundamental knowledge about how astrocytes develop and regulate their growth in the brain, and is expected to provide critical insights into how defects in astrocyte growth or function cause disease.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS053538-08
Application #
8401146
Study Section
Special Emphasis Panel (ZRG1-MDCN-N (02))
Program Officer
Morris, Jill A
Project Start
2006-01-01
Project End
2015-12-31
Budget Start
2013-01-01
Budget End
2013-12-31
Support Year
8
Fiscal Year
2013
Total Cost
$347,250
Indirect Cost
$136,156
Name
University of Massachusetts Medical School Worcester
Department
Biology
Type
Schools of Medicine
DUNS #
603847393
City
Worcester
State
MA
Country
United States
Zip Code
01655
Stork, Tobias; Sheehan, Amy; Tasdemir-Yilmaz, Ozge E et al. (2014) Neuron-glia interactions through the Heartless FGF receptor signaling pathway mediate morphogenesis of Drosophila astrocytes. Neuron 83:388-403
Tasdemir-Yilmaz, Ozge E; Freeman, Marc R (2014) Astrocytes engage unique molecular programs to engulf pruned neuronal debris from distinct subsets of neurons. Genes Dev 28:20-33
Kerr, Kimberly S; Fuentes-Medel, Yuly; Brewer, Cassandra et al. (2014) Glial wingless/Wnt regulates glutamate receptor clustering and synaptic physiology at the Drosophila neuromuscular junction. J Neurosci 34:2910-20
Muthukumar, Allie K; Stork, Tobias; Freeman, Marc R (2014) Activity-dependent regulation of astrocyte GAT levels during synaptogenesis. Nat Neurosci 17:1340-50
Doherty, Johnna; Sheehan, Amy E; Bradshaw, Rachel et al. (2014) PI3K signaling and Stat92E converge to modulate glial responsiveness to axonal injury. PLoS Biol 12:e1001985
Corty, Megan M; Freeman, Marc R (2013) Cell biology in neuroscience: Architects in neural circuit design: glia control neuron numbers and connectivity. J Cell Biol 203:395-405
Macdonald, J M; Doherty, J; Hackett, R et al. (2013) The c-Jun kinase signaling cascade promotes glial engulfment activity through activation of draper and phagocytic function. Cell Death Differ 20:1140-8
Coutinho-Budd, Jaeda; Freeman, Marc R (2013) Probing the enigma: unraveling glial cell biology in invertebrates. Curr Opin Neurobiol 23:1073-9
Logan, Mary A; Hackett, Rachel; Doherty, Johnna et al. (2012) Negative regulation of glial engulfment activity by Draper terminates glial responses to axon injury. Nat Neurosci 15:722-30
Freeman, Marc R (2010) Specification and morphogenesis of astrocytes. Science 330:774-8

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