Biomedical subjects

C Michael Jones

Publications and source records attributed to C Michael Jones.

6 recordsLinked to original sources

PubMed2006

Emergence of organizer function: a lot of "stuff" involved.

Spemann's Organizer is a critical signaling center for patterning the embryo. It arises during blastula stages through the combined influences of dorsal modifying signals and general mesendoderm inducers. Dorsal modifying signals require the nuclear accumulation of beta-catenin, but how this is initiated remained a mystery until recently. New findings now demonstrate that maternal Wnt11 activates the canonical Wnt signaling pathway and is essential for organizer formation. Furthermore, two of the earliest identified mesendoderm inducers, activin and Vg-1, have now been shown to be required for induction of a fully functional organizer. Finally, while it has been clear for a number of years that the Organizer secretes a cocktail of growth factor antagonists, their necessity for organizer function has been in question. Their requirement has now been demonstrated through a multiple "knockdown" approach in frog embryos. Here, we discuss the impact these recent findings have on our understanding of formation and function of the Organizer.

Activins↗

PubMed2005

The NLRR gene family and mouse development: Modified differential display PCR identifies NLRR-1 as a gene expressed in early somitic myoblasts.

During vertebrate embryogenesis, the somites form by segmentation of the trunk mesoderm, lateral to the neural tube, in an anterior to posterior direction. Analysis of differential gene expression during somitogenesis has been problematic due to the limited amount of tissue available from early mouse embryos. To circumvent these problems, we developed a modified differential display PCR technique that is highly sensitive and yields products that can be used directly as in situ hybridisation probes. Using this technique, we isolated NLRR-1 as a gene expressed in the myotome of developing somites but not in the presomitic mesoderm. Detailed expression analysis showed that this gene was expressed in the skeletal muscle precursors of the myotome, branchial arches and limbs as well as in the developing nervous system. Somitic expression occurs in the earliest myoblasts that originate from the dorsal lip in a pattern reminiscent of the muscle determination gene Myf5, but not at the ventral lip, indicating that NLRR-1 is expressed in a subset of myotome cells. The NLRR genes comprise a three-gene family encoding glycosylated transmembrane proteins with external leucine-rich repeats, a fibronectin domain, an immunoglobulin domain and short intracellular tails capable of mediating protein-protein interaction. Analysis of NLRR-3 expression revealed regulated expression in the neural system in developing ganglia and motor neurons. NLRR-2 expression appears to be predominately confined to the adult. The regulated embryonic expression and cellular location of these proteins suggest important roles during mouse development in the control of cell adhesion, movement or signalling.

Amino Acid Sequence↗

PubMed2004

Mechanism of activation of the RAF-ERK signaling pathway by oncogenic mutations of B-RAF.

Over 30 mutations of the B-RAF gene associated with human cancers have been identified, the majority of which are located within the kinase domain. Here we show that of 22 B-RAF mutants analyzed, 18 have elevated kinase activity and signal to ERK in vivo. Surprisingly, three mutants have reduced kinase activity towards MEK in vitro but, by activating C-RAF in vivo, signal to ERK in cells. The structures of wild type and oncogenic V599EB-RAF kinase domains in complex with the RAF inhibitor BAY43-9006 show that the activation segment is held in an inactive conformation by association with the P loop. The clustering of most mutations to these two regions suggests that disruption of this interaction converts B-RAF into its active conformation. The high activity mutants signal to ERK by directly phosphorylating MEK, whereas the impaired activity mutants stimulate MEK by activating endogenous C-RAF, possibly via an allosteric or transphosphorylation mechanism.

Allosteric Regulation↗

PubMed2003

Polycythemia vera responds to imatinib mesylate.

We report 2 patients with polycythemia vera who were demonstrated to be -negative and were unable to tolerate either hydroxyurea or interferon-alpha but who had excellent clinical responses to imatinib mesylate (STI-571). This effect is consistent with the inhibitory effect of imatinib mesylate on c-kit's tyrosine kinase activity as demonstrated by its effectiveness in patients with gastrointestinal stromal tumors.

Adult↗

PubMed2003

Wise, a context-dependent activator and inhibitor of Wnt signalling.

We have isolated a novel secreted molecule, Wise, by a functional screen for activities that alter the anteroposterior character of neuralised Xenopus animal caps. Wise encodes a secreted protein capable of inducing posterior neural markers at a distance. Phenotypes arising from ectopic expression or depletion of Wise resemble those obtained when Wnt signalling is altered. In animal cap assays, posterior neural markers can be induced by Wnt family members, and induction of these markers by Wise requires components of the canonical Wnt pathway. This indicates that in this context Wise activates the Wnt signalling cascade by mimicking some of the effects of Wnt ligands. Activation of the pathway was further confirmed by nuclear accumulation of beta-catenin driven by Wise. By contrast, in an assay for secondary axis induction, extracellularly Wise antagonises the axis-inducing ability of Wnt8. Thus, Wise can activate or inhibit Wnt signalling in a context-dependent manner. The Wise protein physically interacts with the Wnt co-receptor, lipoprotein receptor-related protein 6 (LRP6), and is able to compete with Wnt8 for binding to LRP6. These activities of Wise provide a new mechanism for integrating inputs through the Wnt coreceptor complex to modulate the balance of Wnt signalling.

Activins↗

PubMed2002

Xhex-expressing endodermal tissues are essential for anterior patterning in Xenopus.

Two regions expressing Hex in the early gastrula contribute to organizing the anterior of the vertebrate embryo. In Xenopus, these include the anterior yolky endoderm and the suprablastoporal endoderm (SBE), which is fated to form the epithelial lining of the gut. These tissues may correspond to the anterior visceral endoderm and anterior definitive endoderm of amniotes. Genetic studies in mice have demonstrated the important roles of these tissues in producing anterior identity in the adjacent neural ectoderm. In Xenopus, both the anterior endoderm and the SBE have anterior inducing properties; furthermore, the SBE can organize a full anterior-posterior axis. Inhibition of Xhex function shows that both these Xhex-expressing endodermal tissues are required for anterior development in Xenopus.

Animals↗