Editors' ChoiceNeurogenesis

Toll-Like Receptors and Neural Stem Cells

STKE  11 Sep 2007:
Vol. 2007, Issue 403, pp. tw327
DOI: 10.1126/stke.4032007tw327

The mechanisms underlying the development of new neurons in the adult brain, a process known as neurogenesis, are unclear. Rolls et al. found that Toll-like receptor 2 (TLR2) was abundant in neurogenic niches of the adult human brain, such as the hippocampus, and so investigated the role of TLR2 in neurogenesis. TLR2-deficient (TLR2D) mice showed similar incorporation of the cell proliferation marker 5-bromodeoxyuridine (BrdU) in the dentate gyrus compared with wild-type mice, as determined by microscopic analysis of brain slices. Immunohistochemical analyses showed that neural progenitor cells (NPCs) from TLR2D mice differentiated into fewer neurons but more astrocytes than did NPCs from wild-type mice. TLR2 was detected in wild-type NPCs, and experiments involving wild-type or TLR2D NPCs cocultured with wild-type or TLR2D glial cells showed that it was the TLR2 in NPCs that was important in determining NPC fate. Treatment of wild-type, but not TLR2D, NPCs with the TLR2 agonist Pam3 [N-palmitoyl-S-(2,3-bis(palmitoyloxy)-(2RS)-propyl)-Cys-Ser-Lys4] resulted in differentiation into neurons. Western blotting and immunohistochemistry showed that Pam3 activated IκB kinase and stimulated the nuclear translocation of nuclear factor κB (NF-κB). TLR4 was also detected in NPCs, and their treatment with the TLR4 agonist lipopolysaccharide (LPS) inhibited their differentiation into neurons. NPCs in the hippocampi of TLR4D mice showed increased proliferation and neuronal differentiation compared with those in the hippocampi of wild-type (and TLR2D) mice. Applying neutralizing antibodies against both TLR2 and TLR4 resulted in the increased proliferation and differentiation of wild-type NPCs into neurons, suggesting that TLR4 is the dominant receptor. Together, these data suggest that whereas TLR2 modulates differentiation of NPCs, TLR4 affects both their proliferation and differentiation. Martino and Pluchino provide commentary.

A. Rolls, R. Shechter, A. London, Y. Ziv, A. Ronen, R. Levy, M. Schwartz, Toll-like receptors modulate adult hippocampal neurogenesis. Nat. Cell Biol. 9, 1081-1088 (2007). [PubMed]

G. Martino, S. Pluchino, Neural stem cells: guardians of the brain. Nat. Cell Biol. 9, 1031-1034 (2007). [PubMed]