Figure 1.
Inter-region distances are minimized around birth.
(A) The data: ISH for each gene was performed at eight time points during development. Shown here are mid-sagittal slices for the gene Hmgn2, taken with permission from Allen Institute for Brain Science. Allen Mouse Brain Atlas [Internet] Available from: http://mouse.brain-map.org/ [17] (B) Mean pair-wise dissimilarities between the regions. The curve is a second-order polynomial which minimizes the squared error of the fit to the data. Error bars encompass data within 1.5 times the inter-quartile range, and the boxes show the lower and upper quartiles together with the median. (C) The hourglass shape is robust throughout the dataset: Inter-region distance curve was calculated for the data withholding top k most variable genes for each time point. Error bars represent standard error between brain regions. (D) The hourglass shape is robust throughout the brain. Inter-region distance curve was calculated for the data withholding one region at a time. The blue curve is the mean across brain regions, error bars represent standard deviations from mean. (E) The dissimilarity curve using sets of regions taken from different levels of the reference atlas regional ontology tree, starting from the leaf regions (level 1).
Figure 2.
Functional characterization of hourglass shape.
(A), (B) Clusters of gene profiles that are functionally enriched. Each profile is a measure of contribution to dissimilarity D (see Methods). Black bold curve is the mean of the cluster. Blue lines - all the genes in the cluster; red lines - genes that are in the cluster and in the category; grey lines - genes that are not in the cluster even though belong to the category. (A) Neuron migration shows decreasing dissimilarity (B) Learning or memory shows a post-natal increase in dissimilarity. (C) Spatial expression of the genes Neurog1 and Neurog2 at E11.5 in 11 coarse regions, selected as neuron differentiation genes with highly similar sequence.
Figure 3.
Changes in dissimilarity across individual brain regions.
Embedding of all regions onto a 2D plane using multidimensional scaling. Each circle corresponds to a brain region, with a size that corresponds to the within-region expression standard deviation and a color that corresponds to its embryonic origins. Red: forebrain, telencephalon; pink: forebrain, diencephalon; cyan: midbrain; blue: hindbrain. Rhombomere 1 and Isthmus in the developing post-natal time points are and the cerebellar cortex and cerebellar nuclei at P56 are marked with a black arrow.
Table 1.
Mean contribution values of GO categories at E11.5 and P28.
Figure 4.
(A) Cross correlation between mouse and human gene expression. The black line is taken from known developmental timeline of the two species based on anchor events [27]. Region-specific dissimilarity curves of four brain regions in mouse and human. (B) mouse thalamus, (C) human mediodorsal nucleus of the thalamus, (D) mouse dorsal pallium, (E) human cortical regions, (F) mouse striatum, (G) human striatum, (H) mouse rhombomere 1 and isthmus and (I) human cerebellar cortex. Error bars denote standard deviation across regions.