Induction of midbrain dopaminergic neurons by Sonic hedgehog.
Midbrain dopaminergic neurons, whose loss in adults results in Parkinson's disease, can be specified during embryonic development by a contact-dependent signal from floor plate cells. Here we show that the amino-terminal product of Sonic hedgehog autoproteolysis (SHH-N), an inductive signal expressed by floor plate cells, can induce dopaminergic neurons in vitro. We show further that manipulations to increase the activity of cyclic AMP-dependent protein kinase A, which is known to antagonize hedgehog signaling, can block dopaminergic neuron induction by floor plate cells. Our results and those of other studies indicate that SHH-N can function in a dose-dependent manner to induce different cell types within the neural tube. Our results also provide the basis for a potential cell transplantation therapy for Parkinson's disease.
Hynes
M
M
Department of Neuroscience, Genentech, Inc., South San Francisco, California 94080, USA.
Porter
J A
JA
Chiang
C
C
Chang
D
D
Tessier-Lavigne
M
M
Beachy
P A
PA
Rosenthal
A
A
D000818:Animals; D002478:Cells, Cultured / Q000378:metabolism; D003470:Culture Media; D017868:Cyclic AMP-Dependent Protein Kinases / Q000819:agonists; D004298:Dopamine / Q000502:physiology*; D004627:Embryonic Induction / Q000502:physiology*; D053823:Hedgehog Proteins; D017403:In Situ Hybridization; D008636:Mesencephalon / Q000166:cytology* / Q000378:metabolism; D051379:Mice; D009474:Neurons / Q000378:metabolism*; D010446:Peptide Fragments / Q000378:metabolism; D011506:Proteins / Q000302:isolation & purification / Q000378:metabolism* / Q000494:pharmacology; D051381:Rats; D011994:Recombinant Proteins / Q000378:metabolism; D015534:Trans-Activators
D003470:Culture Media; D053823:Hedgehog Proteins; D010446:Peptide Fragments; D011506:Proteins; D011994:Recombinant Proteins; D015534:Trans-Activators; D017868:Cyclic AMP-Dependent Protein Kinases; D004298:Dopamine