Abstract
Angiogenesis plays crucial roles in maintaining the complex operation of central nervous system (CNS) development. The architecture of communication between neurogenesis and angiogenesis is essential to maintain normal brain development and function. Hence, any disruption of neuron–vascular communications may lead to the pathophysiology of cerebrovascular diseases and blood–brain barrier (BBB) dysfunction. Here we demonstrate that neural differentiation and communication are required for vascular development. Regarding the cellular and molecular mechanism, our results show that PRDM16 activity determines the production of mature neurons and their specific positions in the neocortex. In the cortical plate (CP), aberrant neurons fail to secrete modular calcium-binding protein 1 (SMOC1), an important neuronal signal that participates in neurovascular communication to regulate CNS angiogenesis. Neuronal SMOC1 interacts with TGFBR1 by activating the transcription factors phospho-Smad2/3 to convey intercellular signals to endothelial cells (ECs) in the TGF-β-Smad signaling pathway. Together, our results highlight a crucial coordinated neurovascular development process orchestrated by PRDM16 and reveal the importance of intimate communication for building the neurovascular network during brain development.
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References
Carmeliet P, Tessier-Lavigne M. Common mechanisms of nerve and blood vessel wiring. Nature. 2005;436:193–200.
Noctor SC, Martinez-Cerdeno V, Ivic L, Kriegstein AR. Cortical neurons arise in symmetric and asymmetric division zones and migrate through specific phases. Nat Neurosci. 2004;7:136–44.
Noctor SC, Flint AC, Weissman TA, Dammerman RS, Kriegstein AR. Neurons derived from radial glial cells establish radial units in neocortex. Nature. 2001;409:714–20.
Cullen M, Elzarrad MK, Seaman S, Zudaire E, Stevens J, Yang MY, et al. GPR124, an orphan G protein-coupled receptor, is required for CNS-specific vascularization and establishment of the blood-brain barrier. Proc Natl Acad Sci USA. 2011;108:5759–64.
Hill J, Cave J. Targeting the vasculature to improve neural progenitor transplant survival. Transl Neurosci. 2015;6:162–7.
Attwell D, Buchan AM, Charpak S, Lauritzen M, Macvicar BA, Newman EA. Glial and neuronal control of brain blood flow. Nature. 2010;468:232–43.
Iadecola C. The pathobiology of vascular dementia. Neuron. 2013;80:844–66.
Zhao Z, Nelson AR, Betsholtz C, Zlokovic BV. Establishment and dysfunction of the blood-brain barrier. Cell. 2015;163:1064–78.
Montagne A, Barnes SR, Sweeney MD, Halliday MR, Sagare AP, Zhao Z, et al. Blood-brain barrier breakdown in the aging human hippocampus. Neuron. 2015;85:296–302.
Drouin-Ouellet J, Sawiak SJ, Cisbani G, Lagace M, Kuan WL, Saint-Pierre M, et al. Cerebrovascular and blood-brain barrier impairments in Huntington’s disease: potential implications for its pathophysiology. Ann Neurol. 2015;78:160–77.
Sweeney MD, Sagare AP, Zlokovic BV. Cerebrospinal fluid biomarkers of neurovascular dysfunction in mild dementia and Alzheimer’s disease. J Cereb Blood Flow Metab. 2015;35:1055–68.
Jakobsson L, van Meeteren LA. Transforming growth factor beta family members in regulation of vascular function: in the light of vascular conditional knockouts. Exp Cell Res. 2013;319:1264–70.
ten Dijke P, Arthur HM. Extracellular control of TGFbeta signalling in vascular development and disease. Nat Rev Mol Cell Biol. 2007;8:857–69.
Gaengel K, Genove G, Armulik A, Betsholtz C. Endothelial-mural cell signaling in vascular development and angiogenesis. Arterioscler Thromb Vasc Biol. 2009;29:630–8.
Garcia CM, Darland DC, Massingham LJ, D’Amore PA. Endothelial cell-astrocyte interactions and TGF beta are required for induction of blood-neural barrier properties. Brain Res Dev Brain Res. 2004;152:25–38.
Goumans MJ, Liu Z, ten Dijke P. TGF-beta signaling in vascular biology and dysfunction. Cell Res. 2009;19:116–27.
Pardali E, Goumans MJ, ten Dijke P. Signaling by members of the TGF-beta family in vascular morphogenesis and disease. Trends Cell Biol. 2010;20:556–67.
Li F, Lan Y, Wang Y, Wang J, Yang G, Meng F, et al. Endothelial Smad4 maintains cerebrovascular integrity by activating N-cadherin through cooperation with Notch. Dev Cell. 2011;20:291–302.
Moya IM, Umans L, Maas E, Pereira PN, Beets K, Francis A, et al. Stalk cell phenotype depends on integration of Notch and Smad1/5 signaling cascades. Dev Cell. 2012;22:501–14.
Sweeney MD, Ayyadurai S, Zlokovic BV. Pericytes of the neurovascular unit: key functions and signaling pathways. Nat Neurosci. 2016;19:771–83.
Ma S, Huang Z. Neural regulation of CNS angiogenesis during development. Front Biol. 2015;10:61–73.
Haigh JJ, Morelli PI, Gerhardt H, Haigh K, Tsien J, Damert A, et al. Cortical and retinal defects caused by dosage-dependent reductions in VEGF-A paracrine signaling. Dev Biol. 2003;262:225–41.
Shen Q, Goderie SK, Jin L, Karanth N, Sun Y, Abramova N, et al. Endothelial cells stimulate self-renewal and expand neurogenesis of neural stem cells. Science. 2004;304:1338–40.
Palmer TD, Willhoite AR, Gage FH. Vascular niche for adult hippocampal neurogenesis. J Comp Neurol. 2000;425:479–94.
Nishikata I, Sasaki H, Iga M, Tateno Y, Imayoshi S, Asou N, et al. A novel EVI1 gene family, MEL1, lacking a PR domain (MEL1S) is expressed mainly in t(1;3)(p36;q21)-positive AML and blocks G-CSF-induced myeloid differentiation. Blood. 2003;102:3323–32.
Fog CK, Galli GG, Lund AH. PRDM proteins: important players in differentiation and disease. Bioessays. 2012;34:50–60.
Mochizuki N, Shimizu S, Nagasawa T, Tanaka H, Taniwaki M, Yokota J, et al. A novel gene, MEL1, mapped to 1p36.3 is highly homologous to the MDS1/EVI1 gene and is transcriptionally activated in t(1;3)(p36;q21)-positive leukemia cells. Blood. 2000;96:3209–14.
Seale P, Conroe HM, Estall J, Kajimura S, Frontini A, Ishibashi J, et al. Prdm16 determines the thermogenic program of subcutaneous white adipose tissue in mice. J Clin Investig. 2011;121:96–105.
Kajimura S, Seale P, Spiegelman BM. Transcriptional control of brown fat development. Cell Metab. 2010;11:257–62.
Seale P, Bjork B, Yang W, Kajimura S, Chin S, Kuang S, et al. PRDM16 controls a brown fat/skeletal muscle switch. Nature. 2008;454:961–7.
Chuikov S, Levi BP, Smith ML, Morrison SJ. Prdm16 promotes stem cell maintenance in multiple tissues, partly by regulating oxidative stress. Nat Cell Biol. 2010;12:999–1006.
Aguilo F, Avagyan S, Labar A, Sevilla A, Lee DF, Kumar P, et al. Prdm16 is a physiologic regulator of hematopoietic stem cells. Blood. 2011;117:5057–66.
Shimada IS, Acar M, Burgess RJ, Zhao Z, Morrison SJ. Prdm16 is required for the maintenance of neural stem cells in the postnatal forebrain and their differentiation into ependymal cells. Genes Dev. 2017;31:1134–46.
Ma S, Kwon HJ, Johng H, Zang K, Huang Z. Radial glial neural progenitors regulate nascent brain vascular network stabilization via inhibition of Wnt signaling. PLoS Biol. 2013;11:e1001469.
Englund C, Fink A, Lau C, Pham D, Daza RA, Bulfone A, et al. Pax6, Tbr2, and Tbr1 are expressed sequentially by radial glia, intermediate progenitor cells, and postmitotic neurons in developing neocortex. J Neurosci. 2005;25:247–51.
Xu B, Zhang Y, Du XF, Li J, Zi HX, Bu JW, et al. Neurons secrete miR-132-containing exosomes to regulate brain vascular integrity. Cell Res. 2017;27:882–97.
Ogunshola OO, Stewart WB, Mihalcik V, Solli T, Madri JA, Ment LR. Neuronal VEGF expression correlates with angiogenesis in postnatal developing rat brain. Brain Res Dev Brain Res. 2000;119:139–53.
Eichmann A, Thomas JL. Molecular parallels between neural and vascular development. Cold Spring Harb Perspect Med. 2013;3:a006551.
Segura I, De Smet F, Hohensinner PJ, de Almodovar CR, Carmeliet P. The neurovascular link in health and disease: an update. Trends Mol Med. 2009;15:439–51.
Williams KC, Zhao RW, Ueno K, Hickey WF. PECAM-1 (CD31) expression in the central nervous system and its role in experimental allergic encephalomyelitis in the rat. J Neurosci Res. 1996;45:747–57.
Yamashita J, Itoh H, Hirashima M, Ogawa M, Nishikawa S, Yurugi T, et al. Flk1-positive cells derived from embryonic stem cells serve as vascular progenitors. Nature. 2000;408:92–6.
Harb R, Whiteus C, Freitas C, Grutzendler J. In vivo imaging of cerebral microvascular plasticity from birth to death. J Cereb Blood Flow Metab. 2013;33:146–56.
Gersdorff N, Muller M, Schall A, Miosge N. Secreted modular calcium-binding protein-1 localization during mouse embryogenesis. Histochem Cell Biol. 2006;126:705–12.
Sherva R, Miller MB, Lynch AI, Devereux RB, Rao DC, Oberman A, et al. A whole genome scan for pulse pressure/stroke volume ratio in African Americans: the HyperGEN study. Am J Hypertens. 2007;20:398–402.
Baizabal JM, Mistry M, Garcia MT, Gomez N, Olukoya O, Tran D, et al. The epigenetic state of PRDM16-regulated enhancers in radial glia controls cortical neuron position. Neuron. 2018;99:239–41.
Awwad K, Hu J, Shi L, Mangels N, Abdel Malik R, Zippel N, et al. Role of secreted modular calcium-binding protein 1 (SMOC1) in transforming growth factor beta signalling and angiogenesis. Cardiovasc Res. 2015;106:284–94.
Duque A, Rakic P. Different effects of bromodeoxyuridine and [3H]thymidine incorporation into DNA on cell proliferation, position, and fate. J Neurosci. 2011;31:15205–17.
Wu KW, Mo JL, Kou ZW, Liu Q, Lv LL, Lei Y, et al. Neurovascular interaction promotes the morphological and functional maturation of cortical neurons. Front Cell Neurosci. 2017;11:290.
Carmeliet P, Jain RK. Molecular mechanisms and clinical applications of angiogenesis. Nature. 2011;473:298–307.
Adams RH, Eichmann A. Axon guidance molecules in vascular patterning. Cold Spring Harb Perspect Biol. 2010;2:a001875.
Quaegebeur A, Lange C, Carmeliet P. The neurovascular link in health and disease: molecular mechanisms and therapeutic implications. Neuron. 2011;71:406–24.
Walchli T, Wacker A, Frei K, Regli L, Schwab ME, Hoerstrup SP, et al. Wiring the vascular network with neural cues: a CNS perspective. Neuron. 2015;87:271–96.
Daneman R, Zhou L, Kebede AA, Barres BA. Pericytes are required for blood-brain barrier integrity during embryogenesis. Nature. 2010;468:562–6.
Argaw AT, Asp L, Zhang J, Navrazhina K, Pham T, Mariani J, et al. Astrocyte-derived VEGF-A drives blood-brain barrier disruption in CNS inflammatory disease. Mult Scler J. 2012;18:125–6.
Inoue M, Iwai R, Tabata H, Konno D, Komabayashi-Suzuki M, Watanabe C, et al. Prdm16 is crucial for progression of the multipolar phase during neural differentiation of the developing neocortex. Development. 2017;144:385–99.
Obermeier B, Daneman R, Ransohoff RM. Development, maintenance and disruption of the blood–brain barrier. Nat Med. 2013;19:1584–96.
Ma S, Santhosh D, Kumar TP, Huang Z. A brain-region-specific neural pathway regulating germinal matrix angiogenesis. Dev Cell. 2017;41:366–81.e4.
Alvarez JI, Katayama T, Prat A. Glial influence on the blood brain barrier. Glia. 2013;61:1939–58.
Saito T. In vivo electroporation in the embryonic mouse central nervous system. Nat Protoc. 2006;1:1552–8.
Vasudevan A, Long JE, Crandall JE, Rubenstein JL, Bhide PG. Compartment-specific transcription factors orchestrate angiogenesis gradients in the embryonic brain. Nat Neurosci. 2008;11:429–39.
Acknowledgements
We thank H.L. offered reagents about the experiments. This work was supported by grants from the National Key R&D Program of China (2019YFA0110300), the National Science Fund for Distinguished Young Scholars (81825006), CAS Strategic Priority Research Program (XDA16010301), the National Natural Science Foundation of China (31730033 and 31621004), and K.C. Wong Education Foundation.
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Su, L., Lei, X., Ma, H. et al. PRDM16 orchestrates angiogenesis via neural differentiation in the developing brain. Cell Death Differ 27, 2313–2329 (2020). https://doi.org/10.1038/s41418-020-0504-5
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DOI: https://doi.org/10.1038/s41418-020-0504-5
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