TitleDysregulation of astrocyte extracellular signaling in Costello syndrome.
Publication TypeJournal Article
Year of Publication2015
AuthorsKrencik R, Hokanson KC, Narayan AR, Dvornik J, Rooney GE, Rauen KA, Weiss LA, Rowitch DH, Ullian EM
JournalSci Transl Med
Date Published2015 May 06
KeywordsAnimals, Astrocytes, Cell Differentiation, Cell Line, Costello Syndrome, Extracellular Matrix, Gene Expression Regulation, Genes, ras, Genotype, Hippocampus, Humans, Induced Pluripotent Stem Cells, Mass Spectrometry, Mice, Mice, Transgenic, Mutation, Neuronal Plasticity, Neurons, Oligonucleotide Array Sequence Analysis, Phenotype, Proteoglycans, ras Proteins, Signal Transduction, Snail Family Transcription Factors, Transcription Factors

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.

Alternate JournalSci Transl Med
PubMed ID25947161
PubMed Central IDPMC4474402
Grant List5R01AR062165 / AR / NIAMS NIH HHS / United States
T32 GM007507 / GM / NIGMS NIH HHS / United States
R01MH099595 / MH / NIMH NIH HHS / United States
DP2 OD007449 / OD / NIH HHS / United States
T32 EY007120 / EY / NEI NIH HHS / United States
EY002162 / EY / NEI NIH HHS / United States
1DP2OD006507 / OD / NIH HHS / United States
/ / Howard Hughes Medical Institute / United States
R01 MH099595 / MH / NIMH NIH HHS / United States
DP2 OD006507 / OD / NIH HHS / United States
R01 AR062165 / AR / NIAMS NIH HHS / United States
P30 EY002162 / EY / NEI NIH HHS / United States