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Id proteins synchronize stemness and anchorage to the niche of neural stem cells

Abstract

Stem-cell functions require activation of stem-cell-intrinsic transcriptional programs and extracellular interaction with a niche microenvironment. How the transcriptional machinery controls residency of stem cells in the niche is unknown. Here we show that Id proteins coordinate stem-cell activities with anchorage of neural stem cells (NSCs) to the niche. Conditional inactivation of three Id genes in NSCs triggered detachment of embryonic and postnatal NSCs from the ventricular and vascular niche, respectively. The interrogation of the gene modules directly targeted by Id deletion in NSCs revealed that Id proteins repress bHLH-mediated activation of Rap1GAP, thus serving to maintain the GTPase activity of RAP1, a key mediator of cell adhesion. Preventing the elevation of the Rap1GAP level countered the consequences of Id loss on NSC–niche interaction and stem-cell identity. Thus, by preserving anchorage of NSCs to the extracellular environment, Id activity synchronizes NSC functions to residency in the specialized niche.

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Figure 1: Deletion of Id genes in the developing neocortex decreases the size of the progenitor pool and alters the cell cycle.
Figure 2: Id proteins regulate self-renewal and proliferation of NSCs.
Figure 3: Enforced differentiation of NSCs following acute loss of Id genes.
Figure 4: Acute loss of Id genes in NSCs impairs cell adhesion and induces bHLH-mediated transcription of Rap1GAP.
Figure 5: Expression of Rap1GAP in the normal cerebral cortex and NSC differentiation.
Figure 6: Expression of Rap1GAP inhibits RAP1 activity and impairs adhesion of NSCs.
Figure 7: Silencing of Rap1GAP restores adhesion of NSCs carrying deletion of Id genes in vitro and in vivo.
Figure 8: Id proteins are required for adhesion of NSCs to the vasculature in the postnatal SVZ.

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Acknowledgements

This work was supported by National Cancer Institute grants R01CA101644 and R01CA131126 (A.L.), R01CA085628 and R01CA127643 (A.I.) and National Institute of Neurological Disorders and Stroke R01NS061776 (A.I.). F.N. is supported by a fellowship from the Italian Ministry of Welfare/Provincia di Benevento. We thank S. Angers for the Venus–Radil expression plasmid.

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Contributions

A.L. and A.I. designed and supervised this study, analysed data and wrote the manuscript. X.Z. generated the conditional Id2-knockout mice. F.N., X.Z., D.S., A.C., R.S. and A.L. carried out experiments. H-s.N. and R.B. generated the conditional Id1-knockout mice. Y.Z. generated the constitutive and conditional Id3-knockout mice. M.L. and D.D.B. performed the computational analysis of the microarray data. All authors discussed the results and commented on the manuscript.

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Correspondence to Antonio Iavarone or Anna Lasorella.

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Niola, F., Zhao, X., Singh, D. et al. Id proteins synchronize stemness and anchorage to the niche of neural stem cells. Nat Cell Biol 14, 477–487 (2012). https://doi.org/10.1038/ncb2490

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