Tight control of cell-cell communication is essential for the generation of a normally patterned embryo. A critical mediator of key cell-cell signaling events during embryogenesis is the highly conserved Wnt family of secreted proteins. Recent biochemical and genetic analyses have greatly enriched our understanding of how Wnts signal, and the list of canonical Wnt signaling components has exploded. The data reveal that multiple extracellular, cytoplasmic, and nuclear regulators intricately modulate Wnt signaling levels. In addition, receptor-ligand specificity and feedback loops help to determine Wnt signaling outputs. Wnts are required for adult tissue maintenance, and perturbations in Wnt signaling promote both human degenerative diseases and cancer. The next few years are likely to see novel therapeutic reagents aimed at controlling Wnt signaling in order to alleviate these conditions.

/pdf/the-wnt-signaling-pathway-in-development-and-disease-z4j8s29ao8.pdf

The Wnt signaling pathway in development and disease.

https://www.cell.com/cell/pdf/S0092-8674(06)01344-4.pdf

Wnt/beta-catenin signaling in development and disease.

The extracellular antagonists of the Wnt signalling pathway can be divided into two broad classes. Both classes of molecule prevent ligand-receptor interactions, but by different mechanisms: members of the first class, which include the sFRP (secreted Frizzled-related protein) family, WIF (Wnt inhibitory factor)-1 and Cerberus, primarily bind to Wnt proteins; the second class comprises certain members of the Dickkopf (Dkk) family, which bind to one subunit of the Wnt receptor complex. In addition, there are other protein interactions that contribute to Wnt antagonist function. Moreover, certain sFRPs and Dkks do not antagonise Wnt function, which suggests that these families have as-yet-undiscovered functions.

/pdf/secreted-antagonists-of-the-wnt-signalling-pathway-2vrrbxxx4o.pdf

Secreted antagonists of the Wnt signalling pathway

The Wnt signalling pathway is an ancient system that has been highly conserved during evolution. It has a crucial role in the embryonic development of all animal species, in the regeneration of tissues in adult organisms and in many other processes. Mutations or deregulated expression of components of the Wnt pathway can induce disease, most importantly cancer. The first gene to be identified that encodes a Wnt signalling component, Int1 (integration 1), was molecularly characterized from mouse tumour cells 25 years ago. In parallel, the homologous gene Wingless in Drosophila melanogaster, which produces developmental defects in embryos, was characterized. Since then, further components of the Wnt pathway have been identified and their epistatic relationships have been defined. This article is a Timeline of crucial discoveries about the components and functions of this essential pathway.

Wnt signalling and its impact on development and cancer

http://www-leland.stanford.edu/%7Ernusse/reviews/GordonNusseJBC.pdf

Wnt Signaling: Multiple Pathways, Multiple Receptors, and Multiple Transcription Factors

In nervous systems with bilateral symmetry, many neurons project axons across the midline to the opposite side. In each segment of the Drosophila embryonic nervous system, axons that display this projection pattern choose one of two distinct tracts: the anterior or posterior commissure. Commissure choice is controlled by Derailed, an atypical receptor tyrosine kinase expressed on axons projecting in the anterior commissure. Here we show that Derailed keeps these axons out of the posterior commissure by acting as a receptor for Wnt5, a member of the Wnt family of secreted signalling molecules. Our results reveal an unexpected role in axon guidance for a Wnt family member, and show that the Derailed receptor is an essential component of Wnt signalling in these guidance events.

Wnt-mediated axon guidance via the Drosophila Derailed receptor

In nervous systems with symmetry about the midline, many neurons project axons from one side to the other Although several of the components controlling midline crossing have been identified1,2,3,4, little is known about how axons choose the appropriate pathway when crossing For example, in the Drosophila embryo axons cross the midline in one of two distinct tracts, the anterior or posterior commissure (AC or PC, respectively) Here we show that the Derailed (Drl) receptor tyrosine kinase is expressed by neurons that project in the AC, and that in the absence of Drl such neurons often project abnormally into the PC Conversely, misexpression of Drl in PC neurons forces them to cross in the AC The behaviour of Drl-misexpressing neurons and the in vivo binding pattern of a soluble Drl receptor probe indicate that Drl acts as a guidance receptor for a repellent ligand present in the PC Our results show that Drl is a novel component in the control of midline crossing

Axon routing across the midline controlled by the Drosophila Derailed receptor

Wnt4 Is a Local Repulsive Cue that Determines Synaptic Target Specificity

The homeobox transcription factor even-skipped regulates netrin-receptor expression to control dorsal motor-axon projections in Drosophila.

The Drosophila Derailed (DRL) receptor tyrosine kinase (RTK) controls key guidance events in the developing nervous system and mesoderm. Like other members of the "related to tyrosine kinases" (RYK) subfamily of RTKs, DRL has several highly unusual amino acid substitutions within the catalytic domain, raising the possibility that members of this subfamily are catalytically inactive. To test the role of DRL kinase activity in vivo, we mutated the invariant lysine required for catalytic activity of known kinases and examined the ability of this mutant to function in two assays: a dominant gain-of-function axon switch assay in the nervous system and phenotypic rescue of muscle attachment in drl mutants. We show that this predicted kinase-deficient DRL mutant is capable of functioning in both assays. Our results indicate that DRL does not require kinase activity in vivo and suggest that members of the RYK subfamily of RTKs transduce signals unconventionally.

https://www.jneurosci.org/content/jneuro/21/1/RC119.full.pdf

Shingo Yoshikawa

Papers

Wnt-mediated axon guidance via the Drosophila Derailed receptor

Axon routing across the midline controlled by the Drosophila Derailed receptor

Wnt4 Is a Local Repulsive Cue that Determines Synaptic Target Specificity

The homeobox transcription factor even-skipped regulates netrin-receptor expression to control dorsal motor-axon projections in Drosophila.

The Derailed Guidance Receptor Does Not Require Kinase Activity In Vivo