A mitogen gradient of dorsal midline Wnts organizes growth in the CNS.
Cell cycle progression and exit must be precisely patterned during development to generate tissues of the correct size, shape and symmetry. Here we present evidence that dorsal-ventral growth of the developing spinal cord is regulated by a Wnt mitogen gradient. Wnt signaling through the beta-catenin/TCF pathway positively regulates cell cycle progression and negatively regulates cell cycle exit of spinal neural precursors in part through transcriptional regulation of cyclin D1 and cyclin D2. Wnts expressed at the dorsal midline of the spinal cord, Wnt1 and Wnt3a, have mitogenic activity while more broadly expressed Wnts do not. We present several lines of evidence suggesting that dorsal midline Wnts form a dorsal to ventral concentration gradient. A growth gradient that correlates with the predicted gradient of mitogenic Wnts emerges as the neural tube grows with the proliferation rate highest dorsally and the differentiation rate highest ventrally. These data are rationalized in a 'mitogen gradient model' that explains how proliferation and differentiation can be patterned across a growing field of cells. Computer modeling demonstrates this model is a robust and self-regulating mechanism for patterning cell cycle regulation in a growing tissue. Supplemental data available on-line
Megason
Sean G
SG
Department of Molecular and Cellular Biology, Harvard University, Cambridge, MA 02138, USA.
McMahon
Andrew P
AP
D000818:Animals; D030801:Animals, Genetically Modified; D019521:Body Patterning / Q000235:genetics / Q000502:physiology; D002453:Cell Cycle; D002490:Central Nervous System / Q000196:embryology*; D002642:Chick Embryo; D003198:Computer Simulation; D019938:Cyclin D1 / Q000235:genetics / Q000502:physiology; D056742:Cyclin D2; D016213:Cyclins / Q000235:genetics / Q000502:physiology; D003598:Cytoskeletal Proteins / Q000235:genetics / Q000502:physiology; D006801:Humans; D051379:Mice; D008934:Mitogens / Q000378:metabolism; D008959:Models, Neurological; D009474:Neurons / Q000166:cytology; D011506:Proteins / Q000235:genetics / Q000502:physiology; D011518:Proto-Oncogene Proteins / Q000235:genetics / Q000502:physiology*; D015398:Signal Transduction; D051820:TCF Transcription Factors; D015534:Trans-Activators; D058118:Transcription Factor 7-Like 2 Protein; D014157:Transcription Factors / Q000235:genetics / Q000502:physiology; D014162:Transfection; D051153:Wnt Proteins; D051155:Wnt1 Protein; D060508:Wnt3 Protein; D060509:Wnt3A Protein; D029961:Zebrafish Proteins; D051176:beta Catenin
C080336:CCND2 protein, human; C495270:CTNNB1 protein, human; C495267:CTNNB1 protein, mouse; C486196:Ccnd2 protein, mouse; D056742:Cyclin D2; D016213:Cyclins; D003598:Cytoskeletal Proteins; D008934:Mitogens; D011506:Proteins; D011518:Proto-Oncogene Proteins; D051820:TCF Transcription Factors; C544894:TCF7L2 protein, human; C544895:Tcf7l2 protein, mouse; D015534:Trans-Activators; D058118:Transcription Factor 7-Like 2 Protein; D014157:Transcription Factors; C495247:WNT1 protein, human; C555510:WNT3A protein, human; D051153:Wnt Proteins; D051155:Wnt1 Protein; C495246:Wnt1 protein, mouse; D060508:Wnt3 Protein; D060509:Wnt3A Protein; C555511:Wnt3a protein, mouse; D029961:Zebrafish Proteins; D051176:beta Catenin; D019938:Cyclin D1