SUMMARYCells in the pluripotent ground state can give rise to somatic cells and germ cells, and the acquisition of pluripotency is dependent on the expression of Nanog. Pluripotency is conserved in the primitive ectoderm of embryos from mammals and urodele amphibians, and here we report the isolation of a Nanog ortholog from axolotls (axNanog). axNanog does not contain a tryptophan repeat domain and is expressed as a monomer in the axolotl animal cap. The monomeric form is sufficient to regulate pluripotency in mouse embryonic stem cells, but axNanog dimers are required to rescue LIF-independent self-renewal. Our results show that protein interactions mediated by Nanog dimerization promote proliferation. More importantly, they demonstrate that the mechanisms governing pluripotency are conserved from urodele amphibians to mammals.

Tandem duplications involving the BRAF kinase gene have recently been identified as the most frequent genetic alteration in sporadic pediatric glioma, creating a novel fusion protein (f-BRAF) with increased BRAF activity. To define the role of f-BRAF in gliomagenesis, we demonstrate that f-BRAF regulates neural stem cell (NSC), but not astrocyte, proliferation and is sufficient to induce glioma-like lesions in mice. Moreover, f-BRAF-driven NSC proliferation results from tuberin/Rheb-mediated mammalian target of rapamycin (mTOR) hyperactivation, leading to S6-kinase-dependent degradation of p27. Collectively, these results establish mTOR pathway activation as a key growth regulatory mechanism common to both sporadic and familial low-grade gliomas in children.

No abstract

Understanding how mesoderm is specified during development is a fundamental issue in biology, and it has been studied intensively in embryos from Xenopus. The gene regulatory network (GRN) for Xenopus is surprisingly complex and is not conserved in vertebrates, including mammals, which have single copies of the key genes Nodal and Mix. Why the Xenopus GRN should express multiple copies of Nodal and Mix genes is not known. To understand how these expanded gene families evolved, we investigated mesoderm specification in embryos from axolotls, representing urodele amphibians, since urodele embryology is basal to amphibians and was conserved during the evolution of amniotes, including mammals. We show that single copies of Nodal and Mix are required for mesoderm specification in axolotl embryos, suggesting the ancestral vertebrate state. Furthermore, we uncovered a novel genetic interaction in which Mix induces Brachyury expression, standing in contrast to the relationship of these molecules in Xenopus. However, we demonstrate that this functional relationship is conserved in mammals by showing that it is involved in the production of mesoderm from mouse embryonic stem cells. From our results, we produced an ancestral mesoderm (m)GRN, which we suggest is conserved in vertebrates. The results are discussed within the context of a theory in which the evolution of mechanisms governing early somatic development is constrained by the ancestral germ line-soma relationship, in which germ cells are produced by epigenesis.