Different combinations of Notch ligands and receptors regulate V2 interneuron progenitor proliferation and V2a/V2b cell fate determination.
The broad diversity of neurons is vital to neuronal functions. During vertebrate development, the spinal cord is a site of sensory and motor tasks coordinated by interneurons and the ongoing neurogenesis. In the spinal cord, V2-interneuron (V2-IN) progenitors (p2) develop into excitatory V2a-INs and inhibitory V2b-INs. The balance of these two types of interneurons requires precise control in the number and timing of their production. Here, using zebrafish embryos with altered Notch signaling, we show that different combinations of Notch ligands and receptors regulate two functions: the maintenance of p2 progenitor cells and the V2a/V2b cell fate decision in V2-IN development. Two ligands, DeltaA and DeltaD, and three receptors, Notch1a, Notch1b, and Notch3 redundantly contribute to p2 progenitor maintenance. On the other hand, DeltaA, DeltaC, and Notch1a mainly contribute to the V2a/V2b cell fate determination. A ubiquitin ligase Mib, which activates Notch ligands, acts in both functions through its activation of DeltaA, DeltaC, and DeltaD. Moreover, p2 progenitor maintenance and V2a/V2b fate determination are not distinct temporal processes, but occur within the same time frame during development. In conclusion, V2-IN cell progenitor proliferation and V2a/V2b cell fate determination involve signaling through different sets of Notch ligand-receptor combinations that occur concurrently during development in zebrafish.
Graduate School of Science, Nagoya University, Nagoya, Aichi 464-8602, Japan.
Sayumi
S
Okigawa
Graduate School of Pharmaceutical Sciences, Chiba University, Chiba 260-8675, Japan.
Takamasa
T
Mizoguchi
Graduate School of Science, Nagoya University, Nagoya, Aichi 464-8602, Japan.
Makoto
M
Okano
Graduate School of Pharmaceutical Sciences, Chiba University, Chiba 260-8675, Japan.
Haruna
H
Tanaka
Graduate School of Science, Nagoya University, Nagoya, Aichi 464-8602, Japan.
Miho
M
Isoda
Institute of Molecular and Genomic Medicine, National Health Research Institutes, Miaoli County 35053, Taiwan.
Yun-Jin
YJ
Jiang
Division of Molecular and Developmental Biology, National Institute of Genetics, Mishima, Shizuoka 411-8540, Japan.
Maximiliano
M
Suster
National Institutes of Natural Sciences, Okazaki Institute for Integrative Bioscience, National Institute for Physiological Sciences, Higashiyama 5-1, Myodaiji, Okazaki, Aichi 444-8787, Japan.
Shin-Ichi
S
Higashijima
Division of Molecular and Developmental Biology, National Institute of Genetics, Mishima, Shizuoka 411-8540, Japan.
Koichi
K
Kawakami
Graduate School of Science, Nagoya University, Nagoya, Aichi 464-8602, Japan; Graduate School of Pharmaceutical Sciences, Chiba University, Chiba 260-8675, Japan. Electronic address: mito@chiba-u.jp.
Motoyuki
M
Itoh
D000818:Animals; D049109:Cell Proliferation; D018507:Gene Expression Regulation, Developmental; D055786:Gene Knockout Techniques / Q000662:veterinary; D018398:Homeodomain Proteins / Q000378:metabolism; D007395:Interneurons / Q000166:cytology*; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics / Q000378:metabolism; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism; D060172:Morpholinos / Q000235:genetics; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism; D058953:Neural Stem Cells / Q000166:cytology* / Q000378:metabolism; D055495:Neurogenesis / Q000235:genetics*; D051881:Receptor, Notch1 / Q000378:metabolism; D000071656:Receptor, Notch3; D051880:Receptors, Notch / Q000235:genetics* / Q000378:metabolism; D015398:Signal Transduction / Q000235:genetics; D013116:Spinal Cord / Q000166:cytology / Q000196:embryology*; D044767:Ubiquitin-Protein Ligases / Q000378:metabolism; D015027:Zebrafish / Q000196:embryology*; D029961:Zebrafish Proteins / Q000235:genetics / Q000378:metabolism
D018398:Homeodomain Proteins; D047908:Intracellular Signaling Peptides and Proteins; D008565:Membrane Proteins; D060172:Morpholinos; D009419:Nerve Tissue Proteins; C561596:Notch1b protein, zebrafish; C520425:Notch3 protein, zebrafish; D051881:Receptor, Notch1; D000071656:Receptor, Notch3; D051880:Receptors, Notch; D029961:Zebrafish Proteins; C064045:delta protein; C468126:dld protein, zebrafish; C437805:notch1a protein, zebrafish; D044767:Ubiquitin-Protein Ligases; C471932:mib1 protein, zebrafish
Notch signaling; V2 neuron; Zebrafish