title: Dysregulation of astrocyte extracellular signaling in Costello syndrome.
abstract: Astrocytes produce an assortment of signals that promote neuronal maturation according to a precise developmental timeline. Is this orchestrated timing and signaling altered in human neurodevelopmental disorders? To address this question, the astroglial lineage was investigated in two model systems of a developmental disorder with intellectual disability caused by mutant Harvey rat sarcoma viral oncogene homolog (HRAS) termed Costello syndrome: mutant HRAS human induced pluripotent stem cells (iPSCs) and transgenic mice. Human iPSCs derived from patients with Costello syndrome differentiated to astroglia more rapidly in vitro than those derived from wild-type cell lines with normal HRAS, exhibited hyperplasia, and also generated an abundance of extracellular matrix remodeling factors and proteoglycans. Acute treatment with a farnesyl transferase inhibitor and knockdown of the transcription factor SNAI2 reduced expression of several proteoglycans in Costello syndrome iPSC-derived astrocytes. Similarly, mice in which mutant HRAS was expressed selectively in astrocytes exhibited experience-independent increased accumulation of perineuronal net proteoglycans in cortex, as well as increased parvalbumin expression in interneurons, when compared to wild-type mice. Our data indicate that astrocytes expressing mutant HRAS dysregulate cortical maturation during development as shown by abnormal extracellular matrix remodeling and implicate excessive astrocyte-to-neuron signaling as a possible drug target for treating mental impairment and enhancing neuroplasticity.
authors.affiliation: Department of Ophthalmology, University of California, San Francisco, San Francisco, CA 94143, USA.
authors.forename: Robert
authors.initials: R
authors.lastname: Krencik
authors.affiliation: Neuroscience Program, University of California, San Francisco, San Francisco, CA 94143, USA.
authors.forename: Kenton C
authors.initials: KC
authors.lastname: Hokanson
authors.affiliation: Department of Ophthalmology, University of California, San Francisco, San Francisco, CA 94143, USA.
authors.forename: Aditi R
authors.initials: AR
authors.lastname: Narayan
authors.affiliation: Department of Ophthalmology, University of California, San Francisco, San Francisco, CA 94143, USA.
authors.forename: Jill
authors.initials: J
authors.lastname: Dvornik
authors.affiliation: Department of Ophthalmology, University of California, San Francisco, San Francisco, CA 94143, USA.
authors.forename: Gemma E
authors.initials: GE
authors.lastname: Rooney
authors.affiliation: Department of Pediatrics, University of California, Davis, Sacramento, CA 95817, USA.
authors.forename: Katherine A
authors.initials: KA
authors.lastname: Rauen
authors.affiliation: Department of Psychiatry and Institute for Human Genetics, University of California, San Francisco, San Francisco, CA 94143, USA.
authors.forename: Lauren A
authors.initials: LA
authors.lastname: Weiss
authors.affiliation: Department of Pediatrics, Eli and Edythe Broad Institute for Regenerative Medicine and Stem Cell Research, and Howard Hughes Medical Institute, University of California, San Francisco, San Francisco, CA 94143, USA.
authors.forename: David H
authors.initials: DH
authors.lastname: Rowitch
authors.affiliation: Department of Ophthalmology, University of California, San Francisco, San Francisco, CA 94143, USA. Department of Physiology, University of California, San Francisco, San Francisco, CA 94143, USA. UllianE@vision.ucsf.edu.
authors.forename: Erik M
authors.initials: EM
authors.lastname: Ullian
mesh_terms: D000818:Animals; D001253:Astrocytes / Q000166:cytology* / Q000378:metabolism; D002454:Cell Differentiation; D002460:Cell Line; D056685:Costello Syndrome / Q000378:metabolism*; D005109:Extracellular Matrix / Q000378:metabolism*; D005786:Gene Expression Regulation; D011905:Genes, ras; D005838:Genotype; D006624:Hippocampus / Q000378:metabolism; D006801:Humans; D057026:Induced Pluripotent Stem Cells / Q000166:cytology*; D013058:Mass Spectrometry; D051379:Mice; D008822:Mice, Transgenic; D009154:Mutation; D009473:Neuronal Plasticity; D009474:Neurons / Q000166:cytology / Q000378:metabolism; D020411:Oligonucleotide Array Sequence Analysis; D010641:Phenotype; D011509:Proteoglycans / Q000378:metabolism; D015398:Signal Transduction; D000071250:Snail Family Transcription Factors; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism; D018631:ras Proteins / Q000378:metabolism
chemical_list: D011509:Proteoglycans; C000604408:SNAI2 protein, human; C000604449:Snai2 protein, mouse; C000604450:Snai2 protein, rat; D000071250:Snail Family Transcription Factors; D014157:Transcription Factors; D018631:ras Proteins