The developmental transcriptome of the human brain: implications for neurodevelopmental disorders

Abstract

Purpose of review: Recent characterizations of the transcriptome of the developing human brain by several groups have generated comprehensive datasets on coding and noncoding RNAs that will be instrumental for illuminating the underlying biology of complex neurodevelopmental disorders. This review summarizes recent studies successfully utilizing these data to increase our understanding of the molecular mechanisms of pathogenesis.

Recent findings: Several approaches have successfully integrated developmental transcriptome data with gene discovery to generate testable hypotheses about when and where in the developing human brain disease-associated genes converge. Specifically, these include the projection neurons in the prefrontal and primary motor--somatosensory cortex during mid-fetal development in autism spectrum disorder and the frontal cortex during fetal development in schizophrenia.

Summary: Developmental transcriptome data is a key to interpreting disease-associated mutations and transcriptional changes. Novel approaches integrating the spatial and temporal dimensions of these data have increased our understanding of when and where disease occurs. Refinement of spatial and temporal properties and expanding these findings to other neurodevelopmental disorders will provide critical insights for understanding disease biology.

Figure 1. Timeline of major human neurodevelopmental processes based on gene expression trajectories

Expression trajectories of genes associated with major neurodevelopmental processes reflect the occurrence and progression of these processes in the human neocortex (NCX). The expression levels and trajectories have been adopted from Kang et al. (5). These trajectories suggest that the prenatal development is the most dynamic phase of the human brain development. PCW, post-conceptional weeks; M, months; Y, years.

Figure 2. Spatio-temporal resolution of autism spectrum disorder and schizophrenia pathology

A. Autism spectrum disorder (ASD) associated genes converge in deep layer cortical projection neurons in prefrontal and primary motor-somatosensory cortical regions during midfetal development (Willsey et al., 2013). The two midfetal networks from Willsey et al. were combined into one network encompassing all of mid-fetal development (10–24 PCW). High confidence ASD genes are in black, probable ASD genes are in grey, and other co-expressed genes are in white; positive and negative correlations are signified by red and blue, respectively. Adapted from (34). B. Potential schizophrenia risk genes are highly interconnected in the frontal NCX, particularly in dorsolateral and ventrolateral prefrontal cortical regions (DFC and VFC, respectively), during fetal development (35). Starting with the genes from the DFC and VFC gene network identified by Gulsuner and colleagues, co-expression network analysis built a network of 841 genes highly co-expressed during fetal development (13–26 PCW). These genes were ranked by connectivity and the top 25% (210 genes) are plotted here, with the ten most connected genes in black.