MRC National Institute for Medical Research, London
Science for Health
Regulating the fate of axial stem cells
17 February 2011
It has been thought that the neural plate arises from the ectoderm, after its separation from the mesodermal and endodermal lineages. However, recent cell lineage tracing experiments indicate that the caudal neural plate and paraxial mesoderm are generated from common axial stem cells originating from the caudal lateral epiblast (CLE). Tbx6 null mutant mouse embryos which produce ectopic neural tubes at the expense of paraxial mesoderm provide a clue to the regulatory mechanism underlying this neural versus mesodermal fate choice.
In wild-type embryos, enhancer N1 of the neural primordial gene Sox2 is activated in the CLE, and the cells staying in the superficial layer sustain N1 activity and activate Sox2 expression in the neural plate. In contrast, the cells destined to become mesoderm activate Tbx6 and turn off enhancer N1 before migrating into the paraxial mesoderm compartment. In Tbx6 mutant embryos, however, enhancer N1 activity persists in the paraxial mesoderm compartment, eliciting ectopic Sox2 activation and transforming the paraxial mesoderm into neural tubes.
Robin Lovell-Badge (pictured), from NIMR's Division of Stem Cell Biology and Developmental Genetics, and collaborators in Japan investigated the process of ectopic neural tube development from the
presumptive paraxial mesoderm in homozygous Tbx6 mutant embryos. They found evidence that strongly suggests that the activation of Sox2 in the paraxial mesodermal compartment is causative of ectopic neural tube
development in Tbx6 mutant embryos. Indeed, they were also able to show that forced expression of Sox2 in paraxial mesoderm was sufficient to elicit the formation of ectopic neural tissue. This result also highlights the importance of Sox2 in neural induction.
This study indicates that a pool of bipotential precursor cells in the CLE serves as axial stem cells that concordantly produce neural tube and paraxial mesoderm. This characteristic of CLE is continuous with the chordo-neural hinge at later stages. Thus, the three germ layers describe spatial organization of tissues, but do not indicate the process of tissue derivation. Our evidence reinforces the axial stem cell model by providing the mechanistic basis for the fate choice, namely that Tbx6-dependent regulation of Sox2 determines the neural versus mesodermal fates in the axial stem cells derived from the CLE.
Robin Lovell-Badge
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Enhancer N1-dependent paraxial Sox2 expression and ectopic neural tube development in Tbx6-/- embryos, and their suppression in Tbx6-/-;ΔN1/ΔN1 double mutants. a-d.
Original article
Takemoto, T; Uchikawa, M; Yoshida, M; Bell, DM; Lovell-Badge, R; Papaioannou, VE and Kondoh, H (2011)
Tbx6-dependent Sox2 regulation determines neural or mesodermal fate in axial stem cells
Nature 470, (394-398) Abstract
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