Adult neural stem cell cycling in vivo requires thyroid hormone and its alpha receptor.
Thyroid hormones (TH) are essential for brain development. However, information on if and how this key endocrine factor affects adult neurogenesis is fragmentary. We thus investigated the effects of TH on proliferation and apoptosis of stem cells in the subventricular zone (SVZ), as well as on migration of transgene-tagged neuroblasts out of the stem cell niche. Hypothyroidism significantly reduced all three of these processes, inhibiting generation of new cells. To determine the mechanisms relaying TH action in the SVZ, we analyzed which receptor was implicated and whether the effects were played out directly at the level of the stem cell population. The alpha TH receptor (TRalpha), but not TRbeta, was found to be expressed in nestin positive progenitor cells of the SVZ. Further, use of TRalpha mutant mice showed TRalpha to be required to maintain full proliferative activity. Finally, a direct TH transcriptional effect, not mediated through other cell populations, was revealed by targeted gene transfer to stem cells in vivo. Indeed, TH directly modulated transcription from the c-myc promoter reporter construct containing a functional TH response element containing TRE but not from a mutated TRE sequence. We conclude that liganded-TRalpha is critical for neurogenesis in the adult mammalian brain.
Lemkine
G F
GF
UMR CNRS 5166, Evolution des Régulations Endocriniennes, Muséum National d'Histoire Naturelle, Paris, France.
Raj
A
A
Alfama
G
G
Turque
N
N
Hassani
Z
Z
Alegria-Prévot
O
O
Samarut
J
J
Levi
G
G
Demeneix
B A
BA
D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D001921:Brain / Q000166:cytology*; D053148:Caspase 3; D020169:Caspases / Q000032:analysis; D002453:Cell Cycle / Q000187:drug effects / Q000502:physiology*; D002455:Cell Division / Q000187:drug effects; D002465:Cell Movement; D004247:DNA / Q000096:biosynthesis; D005260:Female; D015870:Gene Expression / Q000187:drug effects; D016259:Genes, myc / Q000235:genetics; D006980:Hyperthyroidism; D007037:Hypothyroidism; D051379:Mice; D018345:Mice, Knockout; D009154:Mutation; D011401:Promoter Regions, Genetic / Q000235:genetics; D011993:Recombinant Fusion Proteins; D013234:Stem Cells / Q000166:cytology* / Q000187:drug effects; D037021:Thyroid Hormone Receptors alpha / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D013963:Thyroid Hormones / Q000494:pharmacology / Q000502:physiology*; D014162:Transfection; D014284:Triiodothyronine / Q000494:pharmacology; D001616:beta-Galactosidase / Q000032:analysis / Q000235:genetics
D011993:Recombinant Fusion Proteins; D037021:Thyroid Hormone Receptors alpha; D013963:Thyroid Hormones; D014284:Triiodothyronine; D004247:DNA; D001616:beta-Galactosidase; C505409:Casp3 protein, mouse; D053148:Caspase 3; D020169:Caspases