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eLife Volume 9 ,2020-03-30
Intermediate progenitors support migration of neural stem cells into dentate gyrus outer neurogenic niches
Developmental Biology
Branden R Nelson 1 , 2 Rebecca D Hodge 1 Ray AM Daza 1 Prem Prakash Tripathi 1 Sebastian J Arnold 3 , 4 Kathleen J Millen 1 , 5 Robert F Hevner 1 , 2
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Received 2019-11-20, accepted for publication 2020-03-30, Published 2020-03-30

The hippocampal dentate gyrus (DG) is a unique brain region maintaining neural stem cells (NCSs) and neurogenesis into adulthood. We used multiphoton imaging to visualize genetically defined progenitor subpopulations in live slices across key stages of mouse DG development, testing decades old static models of DG formation with molecular identification, genetic-lineage tracing, and mutant analyses. We found novel progenitor migrations, timings, dynamic cell-cell interactions, signaling activities, and routes underlie mosaic DG formation. Intermediate progenitors (IPs, Tbr2+) pioneered migrations, supporting and guiding later emigrating NSCs (Sox9+) through multiple transient zones prior to converging at the nascent outer adult niche in a dynamic settling process, generating all prenatal and postnatal granule neurons in defined spatiotemporal order. IPs (Dll1+) extensively targeted contacts to mitotic NSCs (Notch active), revealing a substrate for cell-cell contact support during migrations, a developmental feature maintained in adults. Mouse DG formation shares conserved features of human neocortical expansion.


Mouse;dentate gyrus;multiphoton live-imaging;delta - notch;neural stem cell;tbr2 eomes intermediate progenitor;neurogenesis;hippocampus


© 2020, Nelson et al
http://creativecommons.org/licenses/by/4.0/This article is distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use and redistribution provided that the original author and source are credited.


Branden R Nelson,Rebecca D Hodge,Ray AM Daza,Prem Prakash Tripathi,Sebastian J Arnold,Kathleen J Millen,Robert F Hevner. Intermediate progenitors support migration of neural stem cells into dentate gyrus outer neurogenic niches. eLife ,Vol.9(2020)



[1] D Seo, KM Southard, JW Kim, HJ Lee. et al.(2016). A mechanogenetic toolkit for interrogating cell signaling in space and time. Cell.165:1507-1518. DOI: 10.1038/nm.4485.
[2] LA Martin, SS Tan, D Goldowitz. (2002). Clonal architecture of the mouse Hippocampus. The Journal of Neuroscience.22:3520-3530. DOI: 10.1038/nm.4485.
[3] D Kawaguchi, T Yoshimatsu, K Hozumi, Y Gotoh. et al.(2008). Selection of differentiating cells by different levels of delta-like 1 among neural precursor cells in the developing mouse telencephalon. Development.135:3849-3858. DOI: 10.1038/nm.4485.
[4] R Zhang, A Engler, V Taylor. (2018). Notch: an interactive player in neurogenesis and disease. Cell and Tissue Research.371:73-89. DOI: 10.1038/nm.4485.
[5] N Kalebic, C Gilardi, B Stepien, M Wilsch-Bräuninger. et al.(2019). Neocortical expansion due to increased proliferation of basal progenitors is linked to changes in their morphology. Cell Stem Cell.24:535-550. DOI: 10.1038/nm.4485.
[6] L Madisen, T Mao, H Koch, JM Zhuo. et al.(2012). A toolbox of Cre-dependent optogenetic transgenic mice for light-induced activation and silencing. Nature Neuroscience.15:793-802. DOI: 10.1038/nm.4485.
[7] KM Adams Waldorf, EM Olson, BR Nelson, ME Little. et al.(2018b). The aftermath of zika: need for Long-Term monitoring of exposed children. Trends in Microbiology.26:729-732. DOI: 10.1038/nm.4485.
[8] R Zhang, M Boareto, A Engler, A Louvi. et al.(2019). Id4 Downstream of Notch2 Maintains Neural Stem Cell Quiescence in the Adult Hippocampus. Cell Reports.28:1486-1498. DOI: 10.1038/nm.4485.
[9] H Marzban, MR Del Bigio, J Alizadeh, S Ghavami. et al.(2014). Cellular commitment in the developing cerebellum. Frontiers in Cellular Neuroscience.8. DOI: 10.1038/nm.4485.
[10] KM Adams Waldorf, BR Nelson, JE Stencel-Baerenwald, C Studholme. et al.(2018a). Congenital zika virus infection as a silent pathology with loss of neurogenic output in the fetal brain. Nature Medicine.24:368-374. DOI: 10.1038/nm.4485.
[11] M Yoshida, S Assimacopoulos, KR Jones, EA Grove. et al.(2006). Massive loss of Cajal-Retzius cells does not disrupt neocortical layer order. Development.133:537-545. DOI: 10.1038/nm.4485.
[12] AM Intlekofer, A Banerjee, N Takemoto, SM Gordon. et al.(2008). Anomalous type 17 response to viral infection by CD8+ T cells lacking T-bet and eomesodermin. Science.321:408-411. DOI: 10.1038/nm.4485.
[13] M Boldrini, CA Fulmore, AN Tartt, LR Simeon. et al.(2018). Human hippocampal neurogenesis persists throughout aging. Cell Stem Cell.22:589-599. DOI: 10.1038/nm.4485.
[14] DA Berg, Y Su, D Jimenez-Cyrus, A Patel. et al.(2019). A common embryonic origin of stem cells drives developmental and adult neurogenesis. Cell.177:654-668. DOI: 10.1038/nm.4485.
[15] M Betizeau, V Cortay, D Patti, S Pfister. et al.(2013). Precursor diversity and complexity of lineage relationships in the outer subventricular zone of the primate. Neuron.80:442-457. DOI: 10.1038/nm.4485.
[16] F Semerci, WT Choi, A Bajic, A Thakkar. et al.(2017). Lunatic fringe-mediated notch signaling regulates adult hippocampal neural stem cell maintenance. eLife.6. DOI: 10.1038/nm.4485.
[17] CE Scott, SL Wynn, A Sesay, C Cruz. et al.(2010). SOX9 induces and maintains neural stem cells. Nature Neuroscience.13:1181-1189. DOI: 10.1038/nm.4485.
[18] M Sibbe, E Förster, O Basak, V Taylor. et al.(2009). Reelin and Notch1 cooperate in the development of the dentate gyrus. Journal of Neuroscience.29:8578-8585. DOI: 10.1038/nm.4485.
[19] AB Mihalas, GE Elsen, F Bedogni, RAM Daza. et al.(2016). Intermediate progenitor cohorts differentially generate cortical layers and require Tbr2 for timely acquisition of neuronal subtype identity. Cell Reports.16:92-105. DOI: 10.1038/nm.4485.
[20] GS Kwon, AK Hadjantonakis. (2007). Eomes::GFP-a tool for live imaging cells of the trophoblast, primitive streak, and telencephalon in the mouse embryo. Genesis.45:208-217. DOI: 10.1038/nm.4485.
[21] JB Angevine. (1965). Time of neuron origin in the hippocampal region an autoradiographic study in the mouse. Experimental Neurology.2:1-70. DOI: 10.1038/nm.4485.
[22] AB Mihalas, RF Hevner. (2018). Clonal analysis reveals laminar fate multipotency and daughter cell apoptosis of mouse cortical intermediate progenitors. Development.145. DOI: 10.1038/nm.4485.
[23] K Mizutani, K Yoon, L Dang, A Tokunaga. et al.(2007). Differential notch signalling distinguishes neural stem cells from intermediate progenitors. Nature.449:351-355. DOI: 10.1038/nm.4485.
[24] MA Bonaguidi, MA Wheeler, JS Shapiro, RP Stadel. et al.(2011). In Vivo Clonal Analysis Reveals Self-Renewing and Multipotent Adult Neural Stem Cell Characteristics. Cell.145:1142-1155. DOI: 10.1038/nm.4485.
[25] J Altman, SA Bayer. (1990b). Mosaic organization of the hippocampal neuroepithelium and the multiple germinal sources of dentate granule cells. The Journal of Comparative Neurology.301:325-342. DOI: 10.1038/nm.4485.
[26] D Kawaguchi, S Furutachi, H Kawai, K Hozumi. et al.(2013). Dll1 maintains quiescence of adult neural stem cells and segregates asymmetrically during mitosis. Nature Communications.4. DOI: 10.1038/nm.4485.
[27] J Altman, SA Bayer. (1990a). Migration and distribution of two populations of hippocampal granule cell precursors during the perinatal and postnatal periods. The Journal of Comparative Neurology.301:365-381. DOI: 10.1038/nm.4485.
[28] I Khait, Y Orsher, O Golan, U Binshtok. et al.(2016). Quantitative analysis of Delta-like 1 membrane dynamics elucidates the role of contact geometry on notch signaling. Cell Reports.14:225-233. DOI: 10.1038/nm.4485.
[29] JJ Breunig, BR Nelson. (2020). Comprehensive Developmental Neuroscience: Patterning and Cell Type Specification in the Developing CNS and PNS:313-332. DOI: 10.1038/nm.4485.
[30] JJ Breunig, J Silbereis, FM Vaccarino, N Sestan. et al.(2007). Notch regulates cell fate and dendrite morphology of newborn neurons in the postnatal dentate gyrus. PNAS.104:20558-20563. DOI: 10.1038/nm.4485.
[31] O Shaya, U Binshtok, M Hersch, D Rivkin. et al.(2017). Cell-Cell contact area affects notch signaling and Notch-Dependent patterning. Developmental Cell.40:505-511. DOI: 10.1038/nm.4485.
[32] H Shimojo, A Isomura, T Ohtsuka, H Kori. et al.(2016). Oscillatory control of Delta-like1 in cell interactions regulates dynamic gene expression and tissue morphogenesis. Genes & Development.30:102-116. DOI: 10.1038/nm.4485.
[33] JL Mignone, V Kukekov, AS Chiang, D Steindler. et al.(2004). Neural stem and progenitor cells in nestin-GFP transgenic mice. The Journal of Comparative Neurology.469:311-324. DOI: 10.1038/nm.4485.
[34] G Li, H Kataoka, SR Coughlin, SJ Pleasure. et al.(2009). Identification of a transient subpial neurogenic zone in the developing dentate gyrus and its regulation by Cxcl12 and reelin signaling. Development.136:327-335. DOI: 10.1038/nm.4485.
[35] SF Sorrells, MF Paredes, A Cebrian-Silla, K Sandoval. et al.(2018). Human hippocampal neurogenesis drops sharply in children to undetectable levels in adults. Nature.555:377-381. DOI: 10.1038/nm.4485.
[36] EP Moreno-Jiménez, M Flor-García, J Terreros-Roncal, A Rábano. et al.(2019). Adult hippocampal neurogenesis is abundant in neurologically healthy subjects and drops sharply in patients with Alzheimer's disease. Nature Medicine.25:554-560. DOI: 10.1038/nm.4485.
[37] RD Hodge, BR Nelson, RJ Kahoud, R Yang. et al.(2012). Tbr2 is essential for hippocampal lineage progression from neural stem cells to intermediate progenitors and neurons. Journal of Neuroscience.32:6275-6287. DOI: 10.1038/nm.4485.
[38] K Leto, M Arancillo, EBE Becker, A Buffo. et al.(2016). Consensus Paper: Cerebellar Development. The Cerebellum.15:789-828. DOI: 10.1038/nm.4485.
[39] A Sierra, JM Encinas, JJ Deudero, JH Chancey. et al.(2010). Microglia shape adult hippocampal neurogenesis through apoptosis-coupled phagocytosis. Cell Stem Cell.7:483-495. DOI: 10.1038/nm.4485.
[40] E Ladi, JT Nichols, W Ge, A Miyamoto. et al.(2005). The divergent DSL ligand Dll3 does not activate Notch signaling but cell autonomously attenuates signaling induced by other DSL ligands. Journal of Cell Biology.170:983-992. DOI: 10.1038/nm.4485.
[41] JS Snyder. (2019). Recalibrating the relevance of adult neurogenesis. Trends in Neurosciences.42:164-178. DOI: 10.1038/nm.4485.
[42] CY Ho, HM Ames, A Tipton, G Vezina. et al.(2017). Differential neuronal susceptibility and apoptosis in congenital zika virus infection. Annals of Neurology.82:121-127. DOI: 10.1038/nm.4485.
[43] DV Hansen, JH Lui, PR Parker, AR Kriegstein. et al.(2010). Neurogenic radial Glia in the outer subventricular zone of human neocortex. Nature.464:554-561. DOI: 10.1038/nm.4485.
[44] M Anstötz, G Maccaferri. (2020). A toolbox of criteria for distinguishing Cajal-Retzius cells from other neuronal types in the postnatal mouse Hippocampus. Eneuro.7. DOI: 10.1038/nm.4485.
[45] L Baala, S Briault, HC Etchevers, F Laumonnier. et al.(2007). Homozygous silencing of T-box transcription factor EOMES leads to microcephaly with polymicrogyria and corpus callosum agenesis. Nature Genetics.39:454-456. DOI: 10.1038/nm.4485.
[46] B Brunne, S Zhao, A Derouiche, J Herz. et al.(2010). Origin, maturation, and astroglial transformation of secondary radial glial cells in the developing dentate gyrus. Glia.58:1553-1569. DOI: 10.1038/nm.4485.
[47] G Li, L Fang, G Fernández, SJ Pleasure. et al.(2013). The ventral Hippocampus is the embryonic origin for adult neural stem cells in the dentate gyrus. Neuron.78:658-672. DOI: 10.1038/nm.4485.
[48] AJ Crowther, J Song. (2014). Activity-dependent signaling mechanisms regulating adult hippocampal neural stem cells and their progeny. Neuroscience Bulletin.30:542-556. DOI: 10.1038/nm.4485.
[49] SJ Arnold, J Sugnaseelan, M Groszer, S Srinivas. et al.(2009). Generation and analysis of a mouse line harboring GFP in the eomes/Tbr2 locus. Genesis.47:775-781. DOI: 10.1038/nm.4485.
[50] C de Juan Romero, C Bruder, U Tomasello, JM Sanz-Anquela. et al.(2015). Discrete domains of gene expression in germinal layers distinguish the development of gyrencephaly. The EMBO Journal.34:1859-1874. DOI: 10.1038/nm.4485.
[51] C Englund, A Fink, C Lau, D Pham. et al.(2005). Pax6, Tbr2, and Tbr1 are expressed sequentially by radial Glia, intermediate progenitor cells, and postmitotic neurons in developing neocortex. Journal of Neuroscience.25:247-251. DOI: 10.1038/nm.4485.
[52] BR Nelson, RD Hodge, F Bedogni, RF Hevner. et al.(2013). Dynamic interactions between intermediate neurogenic progenitors and radial Glia in embryonic mouse neocortex: potential role in Dll1-Notch signaling. Journal of Neuroscience.33:9122-9139. DOI: 10.1038/nm.4485.
[53] D Stubbs, J DeProto, K Nie, C Englund. et al.(2009). Neurovascular Congruence during Cerebral Cortical Development. Cerebral Cortex.19:i32-i41. DOI: 10.1038/nm.4485.
[54] N Nandagopal, LA Santat, L LeBon, D Sprinzak. et al.(2018). Dynamic ligand discrimination in the notch signaling pathway. Cell.172:869-880. DOI: 10.1038/nm.4485.
[55] M Rickmann, DG Amaral, WM Cowan. (1987). Organization of radial glial cells during the development of the rat dentate gyrus. The Journal of Comparative Neurology.264:449-479. DOI: 10.1038/nm.4485.
[56] C Llinares-Benadero, V Borrell. (2019). Deconstructing cortical folding: genetic, cellular and mechanical determinants. Nature Reviews Neuroscience.20:161-176. DOI: 10.1038/nm.4485.
[57] KJ Yoon, BK Koo, SK Im, HW Jeong. et al.(2008). Mind bomb 1-expressing intermediate progenitors generate notch signaling to maintain radial glial cells. Neuron.58:519-531. DOI: 10.1038/nm.4485.
[58] DA Berg, AM Bond, GL Ming, H Song. et al.(2018). Radial glial cells in the adult dentate gyrus: what are they and where do they come from?. F1000Research.7:277. DOI: 10.1038/nm.4485.
[59] I Imayoshi, A Isomura, Y Harima, K Kawaguchi. et al.(2013). Oscillatory control of factors determining multipotency and fate in mouse neural progenitors. Science.342:1203-1208. DOI: 10.1038/nm.4485.
[60] F Tronche, C Kellendonk, O Kretz, P Gass. et al.(1999). Disruption of the glucocorticoid receptor gene in the nervous system results in reduced anxiety. Nature Genetics.23:99-103. DOI: 10.1038/nm.4485.
[61] BR Nelson, JA Roby, WB Dobyns, L Rajagopal. et al.(2020). Immune evasion strategies used by zika virus to infect the fetal eye and brain. Viral Immunology.33:22-37. DOI: 10.1038/nm.4485.
[62] IM Pimeisl, Y Tanriver, RA Daza, F Vauti. et al.(2013). Generation and characterization of a tamoxifen-inducible eomes(CreER) mouse line. Genesis.51:725-733. DOI: 10.1038/nm.4485.
[63] I Imayoshi, M Sakamoto, M Yamaguchi, K Mori. et al.(2010). Essential roles of notch signaling in maintenance of neural stem cells in developing and adult brains. Journal of Neuroscience.30:3489-3498. DOI: 10.1038/nm.4485.
[64] IK Suzuki, D Gacquer, R Van Heurck, D Kumar. et al.(2018). Human-Specific NOTCH2NL genes expand cortical neurogenesis through Delta/Notch regulation. Cell.173:1370-1384. DOI: 10.1038/nm.4485.
[65] MY Lin, YL Wang, WL Wu, V Wolseley. et al.(2017). Zika virus infects intermediate progenitor cells and Post-mitotic committed neurons in human fetal brain tissues. Scientific Reports.7. DOI: 10.1038/nm.4485.
[66] RD Hodge, AJ Garcia, GE Elsen, BR Nelson. et al.(2013). Tbr2 expression in Cajal-Retzius cells and intermediate neuronal progenitors is required for morphogenesis of the dentate gyrus. Journal of Neuroscience.33:4165-4180. DOI: 10.1038/nm.4485.
[67] O Basak, V Taylor. (2007). Identification of self-replicating multipotent progenitors in the embryonic nervous system by high notch activity and Hes5 expression. European Journal of Neuroscience.25:1006-1022. DOI: 10.1038/nm.4485.
[68] I Imayoshi, T Ohtsuka, D Metzger, P Chambon. et al.(2006). Temporal regulation of cre recombinase activity in neural stem cells. Genesis.44:233-238. DOI: 10.1038/nm.4485.
[69] DA Berg, K-J Yoon, B Will, AY Xiao. et al.(2015). Tbr2-expressing intermediate progenitor cells in the adult mouse Hippocampus are unipotent neuronal precursors with limited amplification capacity under homeostasis. Frontiers in Biology.10:262-271. DOI: 10.1038/nm.4485.
[70] JH Lui, DV Hansen, AR Kriegstein. (2011). Development and evolution of the human neocortex. Cell.146:18-36. DOI: 10.1038/nm.4485.
[71] IT Fiddes, GA Lodewijk, M Mooring, CM Bosworth. et al.(2018). Human-Specific NOTCH2NL genes affect notch signaling and cortical neurogenesis. Cell.173:1356-1369. DOI: 10.1038/nm.4485.
[72] Z Hadjivasiliou, GL Hunter, B Baum. (2016). A new mechanism for spatial pattern formation via lateral and protrusion-mediated lateral signalling. Journal of the Royal Society Interface.13. DOI: 10.1038/nm.4485.
[73] SA Fietz, I Kelava, J Vogt, M Wilsch-Bräuninger. et al.(2010). OSVZ progenitors of human and ferret neocortex are epithelial-like and expand by integrin signaling. Nature Neuroscience.13:690-699. DOI: 10.1038/nm.4485.
[74] C Baek, L Freem, R Goïame, H Sang. et al.(2018). Mib1 prevents notch Cis-inhibition to defer differentiation and preserve neuroepithelial integrity during neural delamination. PLOS Biology.16. DOI: 10.1038/nm.4485.
[75] GA Pilz, S Bottes, M Betizeau, DJ Jörg. et al.(2018). Live imaging of neurogenesis in the adult mouse Hippocampus. Science.359:658-662. DOI: 10.1038/nm.4485.
[76] HF Nijhout, JA Best, MC Reed. (2019). Systems biology of robustness and homeostatic mechanisms. Wiley Interdisciplinary Reviews. Systems Biology and Medicine.11. DOI: 10.1038/nm.4485.
[77] TJ Nowakowski, AA Pollen, C Sandoval-Espinosa, AR Kriegstein. et al.(2016). Transformation of the radial Glia scaffold demarcates two stages of human cerebral cortex development. Neuron.91:1219-1227. DOI: 10.1038/nm.4485.
[78] Z Nicola, K Fabel, G Kempermann. (2015). Development of the adult neurogenic niche in the Hippocampus of mice. Frontiers in Neuroanatomy.9. DOI: 10.1038/nm.4485.