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Combined multiphoton live-cell imaging and molecular systems approaches reveal mosaic contribution of dynamic transiently signaling INPs to the adult Dentate Gyrus NSC niche

ABSTRACT: Here we directly compare for the first time how the longstanding static model of mouse Dentate Gyrus (DG) development compares with a comprehensive high-resolution live-cell multiphoton (live-MPM) imaging approach. We took advantage of multiple fluorescent protein-based cell-type specific reporters to identify Neural Stem Cells (NSC), Intermediate Neurogenic Progenitors (INPs), and Granule Neurons (GNs) to generate live 4D cellular datasets across embryonic, postnatal and adult ages. Live-MPM revealed that INPs and NSCs migrated long distances along multiple routes to seed the SGZ from multiple directions, and from mosaic progenitor zones along the septo-temporal axis of the hippocampus. We found that dynamic INPs processes and interactions contributed to the architecture of both transient and permanent NSC niches during embryonic development, and that INP cellular plasticity is maintained in the adult SGZ NSC niche. We also used a Molecular Systems (MS) approach to determine the basis for maintained INP cellular plasticity that revealed an overlapping signaling network infrastructure based largely on Rho-family mediated regulation of cytoskeletal dynamics. Our combined strategies revealed that dynamic INPs are a major molecular signaling transition state in the adult SGZ, and that Tbr2 expression defines the initial stage of GN commitment. Our novel findings reveal fundamental new insight into one of the most well studied brain regions key for normal cognitive function, and the importance of analyzing the development of live stem cell niches in vivo.

ORGANISM(S): Mus musculus

PROVIDER: GSE50148 | GEO | 2014/08/01

SECONDARY ACCESSION(S): PRJNA217301

REPOSITORIES: GEO

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Project description:The analysis presented here aims at exposing single-cell transcriptome profiles of Drosophila larval brain type II neural stem cells (NSCII) and of their intermediate neural progenitor (INP) cell progeny during normal development and upon brain tumour initiation using the brain tumour (brat) mutant model. We have used brains 24 hours after larval hatching (ALH), a developmental stage when brat INPs (b_INP) have transformed into brain tumour initiating cells, expressing aberrantly the self-renewal transcription factor Deadpan unlike their iINP control counterparts (c_iINP), but have not yet started to overproliferate. iINP will acquire expression of proneural Asense (Ase) becoming mature INPs (m_INPs), yet brat INPs never express Ase and will lead to massive tumour growth (Bello et al., 2008; Boone and Doe, 2008; Bowman et al., 2008). NSCIIs, adjacent smaller iINPs and one mature INP were individually harvested from live freshly dissected brains expressing membrane tagged GFP specifically in NSCII lineages, and single cell transcriptomes obtained as previously described (Bossing et al., 2012; Barros & Bossing, 2022). PCRs confirmed iINPs and INP samples to lack or show ase expression, respectively. Single cell cDNAs were hybridised on whole-genome microarrays in pairs and data processed as indicated below. References: Bello, B.C., Izergina, N., Caussinus, E., and Reichert, H. (2008). Amplification of neural stem cell proliferation by intermediate progenitor cells in Drosophila brain development. Neural Dev 3, 5. Bowman, R.L., Wang, Q., Carro, A., Verhaak, R.G., and Squatrito, M. (2017). GlioVis data portal for visualization and analysis of brain tumor expression datasets. Neuro Oncol 19, 139-141. Boone, J.Q., and Doe, C.Q. (2008). Identification of Drosophila type II neuroblast lineages containing transit amplifying ganglion mother cells. Dev Neurobiol 68, 1185-1195. Bossing, T., Barros, C.S., Fischer, B., Russell, S., and Shepherd, D. (2012). Disruption of microtubule integrity initiates mitosis during CNS repair. Dev Cell 23, 433-440. Barros C.S. & Bossing, T. (2022). Direct isolation of single cells from living brains of Drosophila melanogaster without dissociation for transcriptome analysis. STAR Protoc. Dec 16;3(4):101735.

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Combined multiphoton live-cell imaging and molecular systems approaches reveal mosaic contribution of dynamic transiently signaling INPs to the adult Dentate Gyrus NSC niche

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