ReviewRoles of Wnt proteins in neural development and maintenance
Introduction
Wnt proteins (the name is derived from mouse Int-1 and Drosophila wingless) are a large family of signaling molecules that have well-established roles in regulating embryonic patterning, cell proliferation and cell determination 1, 2•. There are a total of 24 known vertebrate Wnts, with 18 identified in the mouse [3]. They interact with members of the Frizzled family of receptors to activate downstream signaling events through at least two distinct pathways, one of which controls gene transcription and the other Ca2+ fluxes 4, 5, 6•. To date, 11 members of the Frizzled family have been identified in mice which encode for seven transmembrane domain-containing serpentine receptors. Wnt-mediated signaling is also controlled extracellularly by proteins that either potentiate or inhibit receptor activation. As many wnt proteins and frizzled receptors are expressed in both the developing and mature nervous systems [5], this has stimulated much recent work to examine their roles in both neural development and function. In this commentary, we review recent advances in understanding mechanisms of Wnt signaling. Of particular interest, we discuss the recently discovered elaborate mechanisms developed by metazoan organisms to control spatial and temporal signaling by this important family of molecules. Within the embryonic nervous system, recent work shows that Wnt proteins are involved in almost all important patterning events. Surprisingly, Wnt proteins appear to be equally important at later stages of development and in the mature brain. These observations suggest many productive directions for future research by neuroscientists.
Section snippets
Wnt signaling pathways
For several years it has been known that many Wnt proteins activate gene transcription through a pathway controlled by β-catenin 1, 2• (illustrated in Figure 1). Wnt protein binding to Frizzled receptors activates Dishevelled. Activation of Dishevelled results in inhibition of glycogen synthase kinase-3β (GSK-3β), which results in stabilization of β-catenin. Free β-catenin forms nuclear complexes with members of the TCF/LEF transcription factor family to regulate expression of numerous genes [6•
Regulation of Wnt protein expression and action
Given the complexity of the Wnt signal transduction pathway, it is not surprising that many extracellular molecules have been found to regulate Wnt action. Proteins that appear to act as Wnt protein antagonists include the secreted Frizzled related proteins (sFRP), Dickkopf (Dkk), and cerberus (Cer). sFRPs, as their name suggests, are secreted proteins with amino-acid similarity to the Frizzled receptors 3, 32, 33, 34, 35. sFRPs are thought to act as Wnt antagonists by forming nonfunctional
Wnt signaling in development of the nervous system
In recent work, Wnt signaling in Xenopus embryos has been shown to inhibit expression of BMP-4 and thereby activate neural development [49••]. BMP-4 expression had previously been shown to inhibit neural induction of the dorsal ectoderm. Antagonists of BMP-4 secreted by Spemann’s organizer had been shown to control neural induction by inhibition of BMP-4 activity. This more recent work suggests that Wnt signaling contributes to neural induction by repressing BMP-4 expression, which makes the
Downstream targets of Wnt signaling
Despite significant advances in the understanding of Wnt signal transduction, very few downstream targets of this pathway are currently known. Some of these targets include the mab-5 Hox gene in C. elegans [66], Sloppy Paired [67] and Ubx in Drosophila, siamois in Xenopus, and c-MYC in mammalian cells (reviewed in [6•]). All of these known downstream genes are transcriptional factors whose targets are not well characterized, and hence we are left with a large gap in our knowledge on how the
Conclusions
Our understanding of Wnt signaling complexity has advanced tremendously in the last few years. The identification of the Frizzled proteins as Wnt receptors, and the alternative path of Wnt signaling through G-protein mediated calcium release are two of many new findings. In addition, Wnt signaling is now thought to share elements involved in disparate signal transduction pathways. These include interactions with CK I-ϵ, JNK, cAMP-dependent protein kinase, notch signaling, cadherin-mediated cell
Acknowledgements
The authors thank members of their laboratory for many discussions on development, and Elizabeth Grove and Patricia Salinas for providing preprints of papers discussed in this review. Portions of the work from the authors’ laboratory were supported by a grant from the National Institute of Neurological Disease and Stroke (P01-16033, Louis Reichardt, PI) and a Silvio Conte Center grant from the National Institute of Mental Health (Lily Yeh Jan, PI). Louis Reichardt is an Investigator of the
References and recommended reading
Papers of particular interest, published within the annual period of review, have been highlighted as:
• of special interest
•• of outstanding interest
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