Quiescence and activation of stem and precursor cell populations in the subependymal zone of the mammalian brain are associated with distinct cellular and extracellular matrix signals.
The subependymal zone (SEZ) of the lateral ventricles is one of the areas of the adult brain where new neurons are continuously generated from neural stem cells (NSCs), via rapidly dividing precursors. This neurogenic niche is a complex cellular and extracellular microenvironment, highly vascularized compared to non-neurogenic periventricular areas, within which NSCs and precursors exhibit distinct behavior. Here, we investigate the possible mechanisms by which extracellular matrix molecules and their receptors might regulate this differential behavior. We show that NSCs and precursors proceed through mitosis in the same domains within the SEZ of adult male mice--albeit with NSCs nearer ependymal cells--and that distance from the ventricle is a stronger limiting factor for neurogenic activity than distance from blood vessels. Furthermore, we show that NSCs and precursors are embedded in a laminin-rich extracellular matrix, to which they can both contribute. Importantly, they express differential levels of extracellular matrix receptors, with NSCs expressing low levels of alpha6beta1 integrin, syndecan-1, and lutheran, and in vivo blocking of beta1 integrin selectively induced the proliferation and ectopic migration of precursors. Finally, when NSCs are activated to reconstitute the niche after depletion of precursors, expression of laminin receptors is upregulated. These results indicate that the distinct behavior of adult NSCs and precursors is not necessarily regulated via exposure to differential extracellular signals, but rather via intrinsic regulation of their interaction with their microenvironment.
Kazanis
Ilias
I
Department of Pathology, University of Cambridge, Cambridge CB2 1QP, United Kingdom. ik255@cam.ac.uk
Lathia
Justin D
JD
Vadakkan
Tegy J
TJ
Raborn
Eric
E
Wan
Ruiqian
R
Mughal
Mohamed R
MR
Eckley
D Mark
DM
Sasaki
Takako
T
Patton
Bruce
B
Mattson
Mark P
MP
Hirschi
Karen K
KK
Dickinson
Mary E
ME
ffrench-Constant
Charles
C
D053687:Adult Stem Cells / Q000166:cytology* / Q000378:metabolism*; D000818:Animals; D001253:Astrocytes / Q000166:cytology / Q000378:metabolism; D001921:Brain / Q000166:cytology* / Q000378:metabolism*; D002465:Cell Movement / Q000502:physiology; D049109:Cell Proliferation; D004805:Ependyma / Q000166:cytology* / Q000378:metabolism*; D005109:Extracellular Matrix / Q000378:metabolism*; D019012:Integrin beta1 / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018613:Microscopy, Confocal; D008938:Mitosis; D017474:Receptors, Laminin / Q000378:metabolism*
D019012:Integrin beta1; D017474:Receptors, Laminin