Transcriptional profiling defines unique subtypes of transit amplifying neural progenitors within the neonatal mouse...

While significant progress has been made in understanding the heterogeneity in the NSCs, our understanding of similar heterogeneity among the more abundant transit amplifying progenitors is lagging. Our work on the NPs of the neonatal subventricular zone (SVZ) began over a decade ago, when we used antibodies to the 4 antigens, Lex CD133,LeX,CD140a and NG2 and FACs to classify subsets of the neontal SVZ as either multi-potential (MP1, MP2, MP3, MP4 and PFMPs), glial-restricted (GRP1, GRP2, and GRP3), or neuron-astrocyte restricted (BNAP). Using RNAseq we have characterized the distinctive molecular fingerprint of 4 SVZ neural progenitors and compared their gene expression profiles to those of the NSCs. Overall, we identified 1581 genes that were upregulated in at least one NP compared to the NSCs. Of these genes, 796 genes were upregulated in BNAP/GRP1 compared to NSCs; 653 in GRP2/MP3; 440 in GRP3; 527 in PFMPs. One gene in particular that emerged from our analysis that can be used to distinguish the NPs from the NSCs is Etv1, also known as Er81. Interestingly, PFMPs expressed high levels of the transcription factor GSX1, which has been shown to play important roles in regulating interneuron development in the forebrain. PFMPs are also highly express PDGFRα, CSPG4 (NG2+) Olig2 and transcripts for olfactory receptors. PFMPs also express Sox10, Gjb1, Zfp488 and Myt1 which have been shown to be important for oligodendrocyte development. The top transcription factors with unique upregulation in BNAP/GRP1s were Zfp57, Hoxac6, and Zfp955a. Unlike the other NPs, the GRP1 and GRP2 NPs expressed many proteins involved in immune cell function. In contrast, the top downregulated genes in the NPs are those involved in cilia formation, consistent with the loss of cilia as neural stem cells become multipotential progenitors. We performed bionformatic analyses to provide insights into the transcription factor interactions that are likely regulating their development as well as the functional consequences of these diffferences in gene expression. The present work will serve as an important resource for investigators interested in further defining the transit amplifying progenitors of the mammalian SVZ.