Upregulation of neurovascular communication through filamin abrogation promotes ectopic periventricular neurogenesis.
Neuronal fate-restricted intermediate progenitors (IPs) are derived from the multipotent radial glia (RGs) and serve as the direct precursors for cerebral cortical neurons, but factors that control their neurogenic plasticity remain elusive. Here we report that IPs' neuron production is enhanced by abrogating filamin function, leading to the generation of periventricular neurons independent of normal neocortical neurogenesis and neuronal migration. Loss of Flna in neural progenitor cells (NPCs) led RGs to undergo changes resembling epithelial-mesenchymal transition (EMT) along with exuberant angiogenesis that together changed the microenvironment and increased neurogenesis of IPs. We show that by collaborating with β-arrestin, Flna maintains the homeostatic signaling between the vasculature and NPCs, and loss of this function results in escalated Vegfa and Igf2 signaling, which exacerbates both EMT and angiogenesis to further potentiate IPs' neurogenesis. These results suggest that the neurogenic potential of IPs may be boosted in vivo by manipulating Flna-mediated neurovascular communication.
Department of Neurology, Northwestern University Feinberg School of Medicine, Chicago, United States.|Center for Genetic Medicine, Northwestern University Feinberg School of Medicine, Chicago, United States.|Driskill Graduate Program, Northwestern University Feinberg School of Medicine, Chicago, United States.
Shauna L
SL
Houlihan
Department of Neurology, Northwestern University Feinberg School of Medicine, Chicago, United States.|Center for Genetic Medicine, Northwestern University Feinberg School of Medicine, Chicago, United States.|Driskill Graduate Program, Northwestern University Feinberg School of Medicine, Chicago, United States.
Alison A
AA
Lanctot
Department of Neurology, Northwestern University Feinberg School of Medicine, Chicago, United States.|Center for Genetic Medicine, Northwestern University Feinberg School of Medicine, Chicago, United States.
Yan
Y
Guo
Department of Neurology, Northwestern University Feinberg School of Medicine, Chicago, United States.|Center for Genetic Medicine, Northwestern University Feinberg School of Medicine, Chicago, United States.
Yuanyi
0000-0003-2793-3962
Y
Feng
D000818:Animals; D064448:Filamins / Q000172:deficiency / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D018919:Neovascularization, Physiologic; D055495:Neurogenesis; D009457:Neuroglia / Q000502:physiology*; D013234:Stem Cells / Q000502:physiology*; D015854:Up-Regulation
D064448:Filamins
EMT; cerebral cortex; developmental biology; filamin; intermediate progenitor; mouse; neurogenesis; neurovascular; stem cells
Sci Signal. 2014 Sep 23;7(344):re8
25249658
Cell. 2008 Feb 22;132(4):645-60
18295581
Eur J Hum Genet. 2013 May;21(5):494-502
23032111
Neuron. 1998 Dec;21(6):1315-25
9883725
Hum Mol Genet. 2008 Aug 15;17(16):2441-55
18469343
Annu Rev Cell Dev Biol. 2014;30:465-502
25000993
J Biol Chem. 2002 Jun 14;277(24):21998-2009
11909861
Front Oncol. 2014 Dec 11;4:358
25566498
Nat Cell Biol. 2004 Nov;6(11):1034-8
15516996
Nat Rev Neurosci. 2006 Nov;7(11):883-90
17033683
Cell. 2009 Nov 25;139(5):871-90
19945376
Am J Med Genet A. 2011 Sep;155A(9):2236-41
21815255
Proc Natl Acad Sci U S A. 2006 Dec 26;103(52):19836-41
17172441
Methods Mol Biol. 2014;1135:3-20
24510850
J Biol Chem. 2007 Apr 13;282(15):11329-38
17303558
Nat Neurosci. 2004 Feb;7(2):136-44
14703572
Nucleic Acids Res. 1990 Jun 25;18(12):3587-96
2194165
Cereb Cortex. 2009 Oct;19(10):2439-50
19168665
Genesis. 2001 Oct;31(2):85-94
11668683
Pediatr Radiol. 2000 Nov;30(11):748-55
11100490
Hum Mol Genet. 2007 Jul 15;16(14):1661-75
17510210
Brain. 2006 Jul;129(Pt 7):1892-906
16684786
Mol Biol Cell. 2006 Apr;17 (4):1871-9
16467384
Science. 2012 Aug 10;337(6095):746-9
22879516
Am J Med Genet A. 2011 May;155A(5):1140-6
21484998
J Cell Biol. 2007 Sep 24;178(7):1223-35
17893246
PLoS Biol. 2011 Oct;9(10):e1001172
22028625
Cell. 2011 Jul 8;146(1):18-36
21729779
Cell Adh Migr. 2008 Jul-Sep;2(3):167-9
19262109
Nat Neurosci. 2008 Apr;11(4):429-39
18344991
Hum Mol Genet. 2002 Nov 1;11(23):2845-54
12393796
Cell Tissue Res. 2015 Jan;359(1):17-32
25141969
Am J Med Genet A. 2012 Aug;158A(8):1897-901
22740120
Cell. 2008 Nov 14;135(4):714-25
18976803
Mol Cell Biol. 2006 May;26(9):3432-45
16611986
J Neurosci. 2008 Apr 2;28(14):3707-17
18385329
Neuron. 1996 Jan;16(1):77-87
8562093
Neurology. 2009 Sep 8;73(10):742-3
19625704
Nature. 2010 Mar 25;464(7288):554-561
20154730
Acta Neuropathol. 2002 Dec;104(6):649-57
12410386
Hum Mol Genet. 2001 Aug 15;10(17):1775-83
11532987
J Biol Chem. 2002 Mar 29;277(13):11410-5
11777931
Cereb Cortex. 2009 Jul;19 Suppl 1:i32-41
19386634
Dev Cell. 2009 Oct;17 (4):443-58
19853559
Proc Natl Acad Sci U S A. 2012 Dec 11;109 (50):20620-5
23188799
Neurology. 2004 Jul 13;63(1):51-6
15249610
Nat Neurosci. 2004 Aug;7(8):803-11
15273690
Trends Cell Biol. 2010 Feb;20(2):113-23
20061151
Cereb Cortex. 2009 Jul;19 Suppl 1:i70-7
19346271
J Biol Chem. 1998 Nov 27;273(48):31640-3
9822622
J Neurosci. 2002 Aug 1;22(15):6309-14
12151506