Astrocytes, the most abundant cell type in the human brain, participate in virtually every aspect of brain function and often disease progression. Defining the roles of astrocytes in normal and abnormal brain development as well as disease pathogenesis has been significantly hampered by the lack / scarcity of markers that are specific to progenitors and more mature cells of the astroglial lineage as well as those that may signal functional diversity of astrocytes in different brain regions. During our differentiation of human pluripotent stem cells (hPSCs) to neural subtypes, we discovered a glial precursor that generates astrocytes but not neurons and oligodendrocytes. We will use these putative astroglial progenitors to discover markers that are specific to astroglial progenitors, thus enabling prospective identification of astroglial progenitors for the first time. Building upon our decade's experience in directing PSCs to region-specific neuronal subtypes, we have successfully generated enriched populations of region-specific astrocyte subtypes. We will use these astrocyte subtypes to uncover the functional characteristics of regional astrocytes, setting up the foundation for further exploring the effects of astrocytes on neuronal function in particula brain regions under homeostatic and pathological conditions. As a proof-of-principle, we will profile the transcriptome of cortical astrocytes from Fragile X Syndrome (FXS) in which dysfunctional astrocytes may play a role and for which we have established iPSCs, and discern potential functional contribution of astrocytes to neuronal dysfunction that underlies FXS. Along the proposed study, we will establish tools and resources (e.g., transcription profiles, reporter/transgenic lines for astroglial cells) that will enhance studies on astroglial lineage development and their contribution to pathogenesis, and enable therapeutic development for mental disorders by targeting astroglial cells.

Public Health Relevance

The proposed study will uncover markers for cells of the astroglial lineage, generate resources and tools pertaining astrocyte research, and identify faulty astrocyte genes in patients with autism spectrum disorders, thus opening a new avenue for treating autism spectrum disorders.

Agency
National Institute of Health (NIH)
Institute
National Institute of Mental Health (NIMH)
Type
Research Project (R01)
Project #
5R01MH099587-02
Application #
8595339
Study Section
Special Emphasis Panel (ZMH1-ERB-M (06))
Program Officer
Beckel-Mitchener, Andrea C
Project Start
2013-01-01
Project End
2015-12-31
Budget Start
2014-01-01
Budget End
2014-12-31
Support Year
2
Fiscal Year
2014
Total Cost
$257,355
Indirect Cost
$86,355
Name
University of Wisconsin Madison
Department
Neurosciences
Type
Schools of Medicine
DUNS #
161202122
City
Madison
State
WI
Country
United States
Zip Code
53715
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Williams, Emily Cunningham; Zhong, Xiaofen; Mohamed, Ahmed et al. (2014) Mutant astrocytes differentiated from Rett syndrome patients-specific iPSCs have adverse effects on wild-type neurons. Hum Mol Genet 23:2968-80
Liu, Yan; Liu, Huisheng; Sauvey, Conall et al. (2013) Directed differentiation of forebrain GABA interneurons from human pluripotent stem cells. Nat Protoc 8:1670-9