Cell-type specificity of autism risk factors in the developing human brain

  • Awarded: 2018
  • Award Type: Bridge to Independence
  • Award #: 491371

Tomasz Nowakowski and his colleagues recently proposed an updated model of human cortical development through the identification of discrete cell types and analyses of temporally and spatially restricted trajectories of radial glia maturation and neurogenesis in the developing human telencephalon1. These results support a mixed model of topographical, typological and temporal hierarchies governing cell-type diversity in the developing human telencephalon, including distinct cortical-area-specific excitatory neurons emerging prior to sensory experience.

The current project will leverage these findings as well as unpublished work investigating the molecular heterogeneity of human cortex using high-throughput single-cell analyses of gene expression, intercellular interactions and developmental lineage histories to advance our understanding of autism spectrum disorder (ASD) risk factors in the context of basic mechanisms of human cortical development.

Specifically, Nowakowski will utilize single-cell mRNA-seq data to map the activity of the mTor signaling pathway and other ASD-relevant molecular pathways to developmentally relevant cell types and maturation stages. This approach represents a major step forward over traditional methods of bulk tissue sequencing of microdissected anatomical regions, overcoming underpowered issues in the identification of cell types and their maturation stages that may be at risk. In addition, this project will take the innovative approach of studying local niche interactions between a newly defined subtype of radial glia and human microglia with the goal of highlighting a developmental process that may be affected in ASD through an interaction between genetic and environmental risk factors, such as immunological challenges.


1.Nowakowski T.J. et al. Science 358, 1318-1323 (2017) PubMed
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