3alpha,5alpha-Tetrahydroprogesterone (allopregnanolone) and gamma-aminobutyric acid: autocrine/paracrine interactions in the control of neonatal PSA-NCAM+ progenitor proliferation.
The earliest identified neonatal neural progenitors are cells that express the polysialylated form of the neural cell adhesion molecule (PSA-NCAM). One of these progenitors is the early PSA-NCAM+ progenitor (ePSA-NCAM+ progenitor; Gago et al. [2003] Mol Cell Neurosci 22:162-178), which corresponds to a multipotential cell with a default differentiation through glial lineages. The ePSA-NCAM+ progenitor can synthesize the neurosteroid progesterone (PROG) and its reduced metabolite 3alpha,5alpha-tetrahydroprogesterone (3alpha,5alpha-THP, or allopregnanolone; Gago et al. [ 2001] Glia 36:295-308). The latter is a potent positive allosteric modulator of gamma-aminobutyric acid type A (GABAA) receptors. In the present work, we demonstrate that PROG and 3alpha,5alpha-THP both stimulate ePSA-NCAM+ progenitor proliferation. PROG exerted its mitogenic effect indirectly, through its conversion to 3alpha,5alpha-THP, since it could be abolished by an inhibitor of the 5alpha-reductase (L685-273) and mimicked by 3alpha,5alpha-THP. A dose-response curve revealed a bell-shaped effect of 3alpha,5alpha-THP on ePSA-NCAM+ progenitor proliferation, with greatest stimulation at nanomolar concentrations. The mitogenic effect of 3 alpha,5 alpha-THP was mediated by GABAA receptors, insofar as it could be blocked by the selective antagonist bicuculline. ePSA-NCAM+ progenitors indeed expressed mRNAs for GABAA receptor subunits, and GABA enhanced cell proliferation, an effect that was also bicuculline sensitive. Moreover, these cells synthesized GABA, which was involved in a tonic stimulation of their proliferation. These results reveal complex autocrine/paracrine loops in the control of ePSA-NCAM+ progenitor proliferation, involving both neurosteroid and GABA signaling, and suggest a novel key role for 3alpha,5alpha-THP in the development of the nervous system.
Gago
Nathalie
N
INSERM U 488, Bicêtre, France. gagonat@cantv.net
El-Etr
Martine
M
Sananès
Nicole
N
Cadepond
Françoise
F
Samuel
Denise
D
Avellana-Adalid
Virginia
V
Baron-Van Evercooren
Anne
A
Schumacher
Michael
M
D000818:Animals; D000831:Animals, Newborn; D001483:Base Sequence; D002455:Cell Division; D002470:Cell Survival; D002478:Cells, Cultured; D017931:DNA Primers; D004261:DNA Replication; D019006:Neural Cell Adhesion Molecules / Q000502:physiology*; D011280:Pregnanolone / Q000502:physiology*; D012333:RNA, Messenger / Q000235:genetics; D051381:Rats; D017208:Rats, Wistar; D011963:Receptors, GABA-A / Q000235:genetics; D011980:Receptors, Progesterone / Q000235:genetics; D020133:Reverse Transcriptase Polymerase Chain Reaction; D012794:Sialic Acids / Q000502:physiology; D013234:Stem Cells / Q000166:cytology*; D005680:gamma-Aminobutyric Acid / Q000502:physiology*
D017931:DNA Primers; D019006:Neural Cell Adhesion Molecules; D012333:RNA, Messenger; D011963:Receptors, GABA-A; D011980:Receptors, Progesterone; D012794:Sialic Acids; C021319:polysialic acid; D005680:gamma-Aminobutyric Acid; D011280:Pregnanolone