BMP controls nitric oxide-mediated regulation of cell numbers in the developing neural tube.
Balanced cell proliferation and cell death determines neural precursor cell numbers in early stages of neural tube (NT) development. We have previously shown that nitric oxide (NO) regulates cell numbers locally in the NT of eight to 12 somite embryos. Here, we demonstrate that bone morphogenetic protein-4 (BMP-4), which is expressed in the ectoderm and dorsal NT at these developmental stages, induces programmed cell death (PCD) and promotes entry into the S-phase, via nitric oxide synthase (NOS) activity. These effects can be reversed by BMP-4 antagonists, such as follistatin and noggin, or by specific NOS inhibitors, resulting in low NO levels that facilitate mitosis and reduce PCD. Ectopic BMP-4 induction of PCD is restricted to the dorsal NT, whereas promotion of the S-phase is evenly observed across the dorsal-ventral (D-V) axis. Prolonged exposure to either BMP-4 or NOS inhibitors, which results in high or low NO levels, respectively, causes NT defects. The results presented here throw new light on the BMP signaling pathway. The local presence of BMP-4 helps to regulate cell numbers in the developing NT by a NO-mediated pathway, which is essential for normal NT formation.
Traister
A
A
Department of Cell Research and Immunology, The George S Wise Faculty of Life Sciences, Tel Aviv University, Ramat Aviv, Tel Aviv 69978, Israel.
Abashidze
S
S
Gold
V
V
Yairi
R
R
Michael
E
E
Plachta
N
N
McKinnell
I
I
Patel
K
K
Fainsod
A
A
Weil
M
M
D000818:Animals; D017209:Apoptosis / Q000187:drug effects / Q000502:physiology*; D055415:Bone Morphogenetic Protein 4; D019485:Bone Morphogenetic Proteins / Q000378:metabolism*; D002352:Carrier Proteins; D049109:Cell Proliferation / Q000187:drug effects; D002490:Central Nervous System / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D002642:Chick Embryo; D004475:Ectoderm / Q000166:cytology / Q000378:metabolism*; D004627:Embryonic Induction / Q000187:drug effects / Q000502:physiology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D038681:Follistatin / Q000494:pharmacology; D018507:Gene Expression Regulation, Developmental / Q000187:drug effects / Q000502:physiology; D009569:Nitric Oxide / Q000378:metabolism*; D019001:Nitric Oxide Synthase / Q000378:metabolism; D011506:Proteins / Q000494:pharmacology; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology; D000099176:Noggin Protein
D055415:Bone Morphogenetic Protein 4; D019485:Bone Morphogenetic Proteins; D002352:Carrier Proteins; D004791:Enzyme Inhibitors; D038681:Follistatin; D009569:Nitric Oxide; D019001:Nitric Oxide Synthase; D011506:Proteins; D000099176:Noggin Protein