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Enhancing WNT Signaling Restores Cortical Neuronal Spine Maturation and Synaptogenesis in Tbr1 Mutants.

  • Author(s): Fazel Darbandi, Siavash
  • Robinson Schwartz, Sarah E
  • Pai, Emily Ling-Lin
  • Everitt, Amanda
  • Turner, Marc L
  • Cheyette, Benjamin NR
  • Willsey, A Jeremy
  • State, Matthew W
  • Sohal, Vikaas S
  • Rubenstein, John LR
  • et al.
Abstract

Tbr1 is a high-confidence autism spectrum disorder (ASD) gene encoding a transcription factor with distinct pre- and postnatal functions. Postnatally, Tbr1 conditional knockout (CKO) mutants and constitutive heterozygotes have immature dendritic spines and reduced synaptic density. Tbr1 regulates expression of several genes that underlie synaptic defects, including a kinesin (Kif1a) and a WNT-signaling ligand (Wnt7b). Furthermore, Tbr1 mutant corticothalamic neurons have reduced thalamic axonal arborization. LiCl and a GSK3β inhibitor, two WNT-signaling agonists, robustly rescue the dendritic spines and the synaptic and axonal defects, suggesting that this could have relevance for therapeutic approaches in some forms of ASD.

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