Understanding astrocyte regional and functional heterogeneity. (360G-Wellcome-108139_Z_15_Z)

£2,246,774

The mammalian central nervous system (CNS) shows remarkable regional specialization. This organization, reflected in local and long-range neuronal circuit signaling, underlies both functional complexity of the human brain and vulnerability in certain neurological disorders. It is well recognized that neurons are a diversified population with thousands of sub-types to carry out many specialized functions. In contrast, astrocytes, the most prevalent cell type in the brain, are generally assumed to have homogenous functions across brain regions. However, since astrocytes comprise over 50% of total cells in the brain (Nedergaard et al., 2003, Azevedo et al.,2009), they can be considered as major environmental determinants for local/regional circuits and white matter (Corty & Freeman, 2013, Zhang & Barres, 2010, Han et al., 2013). As such, it is timely and important to challenge the conventional paradigm of astrocyte homogeneity. I propose that astrocyte regional and functional diversity regulates the local in mammals and perhaps invertebrates (Freeman & Rowitch, 2013). Prior work from my lab has-specific shown that astrocytes are allocated according to a spatial-segmental template (Tsai et al.,uit function 2012; Fig. 1). But, a critical unanswered question is whether astrocytes are functionally diversified? We recently reported initial evidence for such heterogeneous function at the single gene level; namely, that ventral spinal cord astrocytes are specialized to encode Sema3a, which is required for sensorimotor circuit integrity (Molofsky et al., 2014). Proving generalized astrocyte regional and functional diversification would defy conventional views and provoke a pervasive reassessment of the roles for astrocytes as key regulators of local neural circuit activity. The proposal will feature interactions between a mammalian and fly lab to: (i) comprehensively determine astrocyte molecular and functional heterogeneity in the vertebrate brain and (ii) investigate evolutionarily conserved astroglial functions in Drosophila. We will develop new transgenic tools and reporters for manipulation of genes required for heterogeneous astrocyte functions during CNS development. The studies are intended to establish whether astrocyte regional and functional diversity is valid as a general neurobiological principle.

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Grant Details

Amount Awarded 2246774
Applicant Surname Rowitch
Approval Committee Science Interview Panel
Award Date 2015-07-07T00:00:00+00:00
Financial Year 2014/15
Grant Programme: Title Investigator Award in Science
Internal ID 108139/Z/15/Z
Lead Applicant Prof David Rowitch
Partnership Value 2246774
Planned Dates: End Date 2024-03-31T00:00:00+00:00
Planned Dates: Start Date 2016-11-01T00:00:00+00:00
Recipient Org: Country United Kingdom
Region East of England