Newly generated cells are increased in hippocampus of adult mice lacking a serine protease inhibitor.
BACKGROUND
Neurogenesis in the hippocampal dentate gyrus and the subventricular zone occurs throughout the life of mammals and newly generated neurons can integrate functionally into established neuronal circuits. Neurogenesis levels in the dentate gyrus are modulated by changes in the environment (enrichment, exercise), hippocampal-dependent tasks, NMDA receptor (NMDAR) activity, sonic hedgehog (SHH) and/or other factors.


RESULTS
previously, we showed that Protease Nexin-1 (PN-1), a potent serine protease inhibitor, regulates the NMDAR availability and activity as well as SHH signaling. Compared with wild-type (WT), we detected a significant increase in BrdU-labeled cells in the dentate gyrus of mice lacking PN-1 (PN-1 -/-) both in controls and after running exercise. Patched homologue 1 (Ptc1) and Gli1 mRNA levels were higher and Gli3 down-regulated in mutant mice under standard conditions and to a lesser extent after running exercise. However, the number of surviving BrdU-positive cells did not differ between WT and PN-1 -/- animals. NMDAR availability was altered in the hippocampus of mutant animals after exercise.


CONCLUSIONS
All together our results indicate that PN-1 controls progenitors proliferation through an effect on the SHH pathway and suggest an influence of the serpin on the survival of newly generated neurons through modulation of NMDAR availability.
Lino
Maddalena M
MM
Friedrich Miescher Institute for Biomedical Research, CH-4058 Basel, Switzerland.
Vaillant
Catherine
C
Orolicki
Slobodanka
S
Sticker
Melanie
M
Kvajo
Mirna
M
Monard
Denis
D
D000818:Animals; D015153:Blotting, Western; D002452:Cell Count; D049109:Cell Proliferation; D002470:Cell Survival / Q000502:physiology; D018891:Dentate Gyrus / Q000378:metabolism*; D007150:Immunohistochemistry; D017403:In Situ Hybridization; D051741:Kruppel-Like Transcription Factors / Q000235:genetics / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism; D055495:Neurogenesis / Q000502:physiology*; D009474:Neurons / Q000378:metabolism*; D000072079:Patched Receptors; D000072081:Patched-1 Receptor; D010805:Physical Conditioning, Animal / Q000502:physiology*; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D011956:Receptors, Cell Surface / Q000235:genetics / Q000378:metabolism; D016194:Receptors, N-Methyl-D-Aspartate / Q000235:genetics / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D058258:Serpin E2; D015843:Serpins / Q000235:genetics* / Q000378:metabolism; D000071676:Zinc Finger Protein GLI1; D000074290:Zinc Finger Protein Gli3
C498520:Gli1 protein, mouse; C465571:Gli3 protein, mouse; D051741:Kruppel-Like Transcription Factors; D009419:Nerve Tissue Proteins; D000072079:Patched Receptors; D000072081:Patched-1 Receptor; C000606240:Ptch1 protein, mouse; D012333:RNA, Messenger; D011956:Receptors, Cell Surface; D016194:Receptors, N-Methyl-D-Aspartate; D058258:Serpin E2; C511869:Serpine2 protein, mouse; D015843:Serpins; D000071676:Zinc Finger Protein GLI1; D000074290:Zinc Finger Protein Gli3