Sonic hedgehog and bone morphogenetic protein regulate interneuron development from dorsal telencephalic progenitors in vitro.
Cortical progenitors are competent to produce interneurons, but do not generate large numbers of interneurons in vivo under normal circumstances. This could reflect the absence of an inductive signal in the environment of the dorsal telencephalon and/or the presence of an inhibitory signal. To determine whether either or both mechanisms regulate interneuron generation, progenitors in dorsomedial and dorsolateral wall explants of mouse telencephalon were marked with a retrovirus and cultured under several conditions. When cultured separately, progenitors in dorsomedial wall explants produced fewer GABAergic interneurons than progenitors in dorsolateral wall explants. When cocultured with ventral telencephalic cells, however, dorsomedial wall progenitors produced more GABAergic interneurons than in dorsomedial wall explants alone. The inductive effect of ventral telencephalon depended on sonic hedgehog (Shh) and could be mimicked by exogenous Shh. In contrast, exogenous bone morphogenetic protein 4 (BMP4) reduced the production of interneurons in dorsolateral wall explants and inhibited the induction by exogenous Shh. Moreover, inhibiting BMP signaling in dorsomedial wall progenitors with a dominant-negative BMP receptor Ib (dnBMPIb) virus increased their production of interneurons, even if Shh was blocked. Shh and dnBMPRIb increased proliferation and the generation of interneurons, but FGF2 did not induce interneurons, although it increased proliferation. This suggests that proliferation per se does not control the production of interneurons. Our findings suggest that the generation of interneurons by dorsal telencephalic progenitors is normally limited by excess levels of BMPs. Shh may promote the generation of interneurons by antagonizing BMP, but may not be required directly for the generation of interneurons.
Department of Neurobiology and Pittsburgh Cancer Institute, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania 15261, USA.
Alexandra
A
Gulacsi
Laura
L
Lillien
D000818:Animals; D000943:Antigens, Differentiation / Q000096:biosynthesis; D055415:Bone Morphogenetic Protein 4; D052005:Bone Morphogenetic Protein Receptors, Type I; D019485:Bone Morphogenetic Proteins / Q000494:pharmacology / Q000502:physiology*; D002454:Cell Differentiation / Q000187:drug effects / Q000502:physiology; D002455:Cell Division / Q000502:physiology; D019070:Cell Lineage; D002478:Cells, Cultured; D018014:Gene Transfer Techniques; D005799:Genes, Dominant; D017930:Genes, Reporter; D018698:Glutamic Acid / Q000378:metabolism; D053823:Hedgehog Proteins; D007395:Interneurons / Q000166:cytology* / Q000187:drug effects / Q000378:metabolism; D051379:Mice; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism; D017978:Receptors, Growth Factor / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology; D013234:Stem Cells / Q000166:cytology* / Q000187:drug effects / Q000378:metabolism*; D013687:Telencephalon / Q000166:cytology* / Q000196:embryology; D015534:Trans-Activators / Q000037:antagonists & inhibitors / Q000494:pharmacology / Q000502:physiology*; D014704:Veratrum Alkaloids / Q000494:pharmacology; D005680:gamma-Aminobutyric Acid / Q000378:metabolism
D000943:Antigens, Differentiation; C525810:Bmp4 protein, mouse; D055415:Bone Morphogenetic Protein 4; D019485:Bone Morphogenetic Proteins; D053823:Hedgehog Proteins; D017978:Receptors, Growth Factor; D015534:Trans-Activators; D014704:Veratrum Alkaloids; D018698:Glutamic Acid; D005680:gamma-Aminobutyric Acid; D017346:Protein Serine-Threonine Kinases; D052005:Bone Morphogenetic Protein Receptors, Type I; C000541:cyclopamine