Regulation of survival in adult hippocampal and glioblastoma stem cell lineages by the homeodomain-only protein HOP.
BACKGROUND
Homeodomain proteins play critical roles in shaping the development of the embryonic central nervous system in mammals. After birth, neurogenic activities are relegated to stem cell niches, which include the subgranular layer of the dentate gyrus of the hippocampus. Here, we have analyzed the function of HOP (Homeodomain only protein) in this stem cell niche and in human glioblastomas.


RESULTS
We find that HOP is strongly expressed by radial astrocytes of the dentate gyrus in mice, which are stem cells that give rise to hippocampal granular neurons throughout adulthood. Deletion or down-regulation of HOP results in a decrease of apoptosis of these stem cells without changes in proliferation, and in an increase in the number of newly formed granule neurons. We also find that human glioblastomas largely lack HOP expression and that reintroduction of HOP function in glioma cells cultured as gliomaspheres leads to enhanced apoptosis in a subset of cases. In these cells, HOP function decreases clonogenicity.


CONCLUSIONS
These data suggest that HOP participates in the regulation of the adult mouse hippocampal stem cell niche by negatively affecting cell survival. In addition, HOP may work as a tumor suppressor in a subset of glioblastomas. HOP function thus appears to be critical in the adult brain in a region of continued plasticity, and its deregulation may contribute to disease.
De Toni
Arianna
A
UMR CNRS 8542, ENS, rue d'Ulm, 75005 Paris, France. detoni@biologie.ens.fr
Zbinden
Marie
M
Epstein
Jonathan A
JA
Ruiz i Altaba
Ariel
A
Prochiantz
Alain
A
Caillé
Isabelle
I
D000367:Age Factors; D000818:Animals; D017209:Apoptosis / Q000502:physiology; D001253:Astrocytes / Q000166:cytology / Q000502:physiology; D001932:Brain Neoplasms / Q000473:pathology / Q000503:physiopathology*; D002455:Cell Division / Q000502:physiology; D045744:Cell Line, Tumor; D019070:Cell Lineage / Q000502:physiology; D002470:Cell Survival / Q000502:physiology; D018891:Dentate Gyrus / Q000166:cytology / Q000196:embryology / Q000502:physiology; D018507:Gene Expression Regulation, Developmental; D005909:Glioblastoma / Q000473:pathology / Q000503:physiopathology*; D018398:Homeodomain Proteins / Q000235:genetics* / Q000378:metabolism; D006801:Humans; D051379:Mice; D018345:Mice, Knockout; D034741:RNA, Small Interfering; D013234:Stem Cells / Q000166:cytology / Q000502:physiology*; D025521:Tumor Suppressor Proteins / Q000235:genetics* / Q000378:metabolism
C476884:HOPX protein, human; D018398:Homeodomain Proteins; C466740:Hop protein, mouse; D034741:RNA, Small Interfering; D025521:Tumor Suppressor Proteins