IInteractions between laminins and integrin receptors hold neural stem cells in place at the ventricular surface of embryonic brain. Transient disruption leads to abnormal stem cell divisions and permanent cortical malformation.

Objective LRP1 is a large endocytic and signaling receptor that is abundant in vascular smooth muscle cells (SMC). Mice in which the lrp1 gene is deleted in SMC (smLRP1-/-) on an LDLr-deficient background display excessive PDGF signaling, SMC proliferation, aneurysm formation, and increased susceptibility to atherosclerosis. The objectives of the current studies were to examine the potential of LRP1 to modulate vascular physiology under non-atherogenic conditions. Approach and Results We found smLRP1-/- mice to have extensive in vivo aortic dilatation accompanied by disorganized and degraded elastic lamina along with medial thickening of the arterial vessels resulting from excess matrix deposition. Surprisingly, this was not due to excessive PDGF signaling. Rather, quantitative differential proteomic analysis revealed that smLRP1-/- vessels contain a 4-fold increase in protein levels of high-temperature requirement factor A1 (HtrA1) which is a secreted serine protease that is known to degrade matrix components and to impair elastogenesis resulting in fragmentation of elastic fibers. Importantly, our studies discovered that HtrA1 is a novel LRP1 ligand. Proteomics analysis also identified excessive accumulation of connective tissue growth factor (CTGF), an LRP1 ligand and a key mediator of fibrosis. Conclusions Our findings suggest a critical role for LRP1 in maintaining the integrity of vessels by regulating protease activity as well as matrix deposition by modulating HtrA1 and CTGF protein levels. These studies highlight two new molecules, CTGF and HtrA1, which contribute to detrimental changes in the vasculature and therefore represent new target molecules for potential therapeutic intervention to maintain vessel wall homeostasis.

The mechanisms by which neural and glial progenitor cells in the adult brain respond to tissue injury are unknown. We studied the responses of these cells to stab wound injury in rats and in two transgenic mouse models in which Y/GFP is driven either by Sox2 (a neural stem cell marker) or by Talpha-1 (which marks newly born neurons). The response of neural progenitors was low in all nonneurogenic regions, and no neurogenesis occurred at the injury site. Glial progenitors expressing Olig2 and NG2 showed the greatest response. The appearance of these progenitors preceded the appearance of reactive astrocytes. Surprisingly, we found evidence of the translocation of the transcription factor Olig2 into cytoplasm in the first week after injury, a mechanism that is known to mediate the differentiation of astrocytes during brain development. Translocation of Olig2, down-regulation of NG2, and increased glial fibrillary acidic protein expression were recapitulated in vitro after exposure of glial progenitors to serum components or bone morphogentic protein by up-regulation of Notch-1. The glial differentiation and Olig2 translocation could be blocked by inhibition of Notch-1 with the gamma-secretase inhibitor DAPT. Together, these data indicate that the prompt maturation of numerous Olig2(+) glial progenitors to astrocytes underlies the repair process after a traumatic injury. In contrast, neural stem cells and neuronal progenitor cells appear to play only a minor role in the injured adult CNS.