Pharmacogenomic identification of small molecules for lineage specific manipulation of subventricular zone germinal activity

Abstract

Strategies for promoting neural regeneration are hindered by the difficulty of manipulating desired neural fates in the brain without complex genetic methods. The subventricular zone (SVZ) is the largest germinal zone of the forebrain and is responsible for the lifelong generation of interneuron subtypes and oligodendrocytes. Here, we have performed a bioinformatics analysis of the transcriptome of dorsal and lateral SVZ in early postnatal mice, including neural stem cells (NSCs) and their immediate progenies, which generate distinct neural lineages. We identified multiple signaling pathways that trigger distinct downstream transcriptional networks to regulate the diversity of neural cells originating from the SVZ. Next, we used a novel in silico genomic analysis, searchable platform-independent expression database/connectivity map (SPIED/CMAP), to generate a catalogue of small molecules that can be used to manipulate SVZ microdomain-specific lineages. Finally, we demonstrate that compounds identified in this analysis promote the generation of specific cell lineages from NSCs in vivo, during postnatal life and adulthood, as well as in regenerative contexts. This study unravels new strategies for using small bioactive molecules to direct germinal activity in the SVZ, which has therapeutic potential in neurodegenerative diseases.

From gene networks to drugs: systems pharmacology approaches for AUD

“…To compare the disease and drug signatures the KS-like statistic (as described by (Lamb et al 2006; Subramanian et al 2017) is the most frequently used similarity metric, although several studies also use Spearman or Pearson correlation coefficients (Azim et al 2017; Siavelis et al 2016; So et al 2017) or Fischer’s Exact Test (Delahaye-Duriez et al 2016). Most studies operate under the transcriptional “reversal hypothesis”, which assumes that drugs with negative connectivity scores (i.e., with gene expression signatures that revert the disease’s effects on gene expression to the control state) would ameliorate disease phenotype.…”

“…Azim and colleagues (2017) sought to identify small molecules to mobilize endogenous stem cells and direct their fate as a therapy for neurodegenerative and demyelinating disorders (Azim et al 2017). These studies used the transcriptional signatures of neural stem cells (NSCs) in the ventral/lateral subventricular zone (SVZ) of the dentate gyrus which give rise to interneurons of the olfactory bulb and cortical areas, and of NSCs in the dorsal SVZ which give rise to glutamatergic neurons and oligodendrocytes.…”

“…Even if brain-relevant cell lines were included in the expression profiles of LINCS-L1000 or other databases of drug-related transcriptomes, it is unclear how relevant in vitro results are to the biology of an intact organism, which is why in vivo experimental validation is critical. Only 6 of the 19 studies for brain disease listed in Table 3 performed in vivo validation of the proposed pharmaceutical candidates (Azim et al 2017; Chandran et al 2016; Ferguson et al 2017; Mirza et al 2017; Papassotiropoulos et al 2013; Smalley et al 2016), and none directly tested the underlying assumption of in silico connectivity mapping. Specifically, it is important to address the following question: if a candidate compound is effective in treating a given disease phenotype, was it the result of a reversal in expression of disease-related genes by the compound?…”

A question of fate

“…In this issue of PLOS Biology , Azim and collaborators [16] bring us a step closer to clinically applicable stem-cell therapies by focusing on functional outcomes of NSCs during early postnatal periods: they examined NSC lineages in the SVZ microdomains (dorsal versus ventral/lateral) and identified small molecules that direct the fate of these cells toward neurogenic as opposed to oligodendrogenic lineages.…”

“…Azim et al [16] performed transcriptome analysis of NSCs and TAPs from the discrete SVZ microdomains at several early postnatal time points. They then compared the profiles to identify pathways unique to each set of cells, confirming significant regional specificity in the different populations as well as their propensity toward a certain lineage (neuronal versus oligodendroglial).…”