Fig. 2: Modeling neurodevelopmental perturbations.

A Examples of risk factor gene expression overlaid on developmental trajectories during cell differentiation and maturation, from neural stem cells on the left differentiating towards committed cell types on the right. Red denotes gene expression. B, C The concept of selective vulnerability to environmental and genetic risk factors, based on receiving gene sets, i.e., gene sets that define cellular components (as signaling network) that are necessary to respond to a particular risk factor, as first described in [6]. The response to genetic risk factors originates from within the cell, whereas for environmental risk factors the initial response is transmembrane. The susceptibility to a risk factor can change over the course of development due to changes in expression of receiving gene sets, illustrated by the cells on the right. D Sensitivity to risk factors over development is based on ability to respond to the risk factors. A combinations of two genes that constitute a receiving gene set is shown (dotted lines—gene expression). E Modeling strategies on what to model, and on what not to model. If a genetic (Gen) risk factor/receiving gene set is expressed only during certain period/cell lineage (dashed line), it makes sense to model within this period (black but not red Gen label). Similarly, for an environmental risk factor, only period when receiving gene set is present (dotted lines) is relevant to model (black but not red Env label). F Assessment of conservation of risk factor/receiving gene set expression across models. Left and right columns show examples when mouse in vivo or human in vitro models, respectively, are better in mimicking human in vivo.