UNSW Embryology

Signal Factors - Wnt

© Dr Mark Hill (2010)

Acknowledgements

Introduction

The designation 'Wnt' was derived from two drosophila phenotypes 'wingless' and 'int'. The Wnt gene was first defined as a protooncogene, int1. Humans have at least 4 Wnt genes: Wnt7a gene is at 3p25 encoding a 349aa secreted glycoprotein. A patterning switch with different roles in different tissues. Wnt7a is secreted protein and binds to extracellular matrix. The mechanism of Wnt distribution (free diffusion, restricted diffusion and active transport) and all its possible cell receptors are still being determined. There is at least one WNT receptor called Frizzled (FZD). The Frizzled gene family encodes a seven-transmembrane receptor.

If you are interested in this family of proteins, look also at the WWW page by Roel Nusse called the Wnt gene Homepage. (More? see list of pages below)

Page Links: Introduction | Some Recent Findings | Signaling Pathway | Signaling Factors | OMIM | WWW Links | References | Glossary

Some Recent Findings

Muscle Development - Wnt signaling promotes AChR aggregation at the neuromuscular synapse in collaboration with agrin. Henriquez JP, Webb A, Bence M, Bildsoe H, Sahores M, Hughes SM, Salinas PC. Proc Natl Acad Sci U S A. 2008 Nov 19.

"Wnt proteins regulate the formation of central synapses by stimulating synaptic assembly, but their role at the vertebrate neuromuscular junction (NMJ) is unclear. Wnt3 is expressed by lateral motoneurons of the spinal cord during the period of motoneuron-muscle innervation. ...Wnt3 does not signal through the canonical Wnt pathway to induce cluster formation. Instead, Wnt3 induces the rapid formation of unstable AChR micro-clusters through activation of Rac1, which aggregate into large clusters only in the presence of agrin."

(More? Muscle Development)

Vascular Development - Canonical Wnt signaling regulates organ-specific assembly and differentiation of CNS vasculature. Stenman JM, Rajagopal J, Carroll TJ, Ishibashi M, McMahon J, McMahon AP. Science. 2008 Nov 21;322(5905):1247-50.

"The central nervous system (CNS) vasculature consists of a tightly sealed endothelium that forms the blood-brain barrier, whereas blood vessels of other organs are more porous. Wnt7a and Wnt7b encode two Wnt ligands produced by the neuroepithelium of the developing CNS coincident with vascular invasion. Using genetic mouse models, we found that these ligands directly target the vascular endothelium and that the CNS uses the canonical Wnt signaling pathway to promote formation and CNS-specific differentiation of the organ's vasculature"

(More? Vascular Development)

Signaling Pathway

At least 3 separate signaling pathways have been identified in relation to Wnt singnaling.

1. Canonical pathway
2. Non-canonical or planar cell polarity pathway
3. Wnt-Calcium ion pathway

Canonical Pathway

1. Wnt binds the surface receptor Frizzled (Fz) and LRP5/6 receptor complex
2. Induces the stabilization of beta-catenin (through the DIX and PDZ domains of Dishevelled and other factors including Axin, glycogen synthase kinase 3 and casein kinase 1)
3. Beta-catenin translocates into the nucleus
4. Beta-catenin complexes with members of the LEF/TCF family of transcription factors.
5. Transcriptional induction of target genes.
6. Beta-catenin is then exported from the nucleus and degraded via the proteosomal machinery.

Non-Canonical (Planar Cell Polarity Pathway)

1. Wnt binds the surface receptor Frizzled (Fz) independent of the LRP5/6 receptor complex.
2. Acts through Dishevelled (PDZ and DEP domains)
3. Mediates cytoskeletal (microfilament) changes through activation of the small GTPases Rho and Rac.

Wnt-Calcium Ion Pathway

1. Wnt binds the surface receptor Frizzled (Fz) and mediates activation of heterotrimeric G-proteins.
2. Acts internally through Dsh, phospholipase C, calcium-calmodulin kinase 2 (CamK2) and protein kinase C (PKC).
3. has various cellular functions including cell adhesion and motility.

Signaling Factors

• FUNCTION: PROBABLE DEVELOPMENTAL PROTEIN. SIGNALING BY WNT-7A ALLOWS SEXUALLY DIMORPHIC DEVELOPMENT OF THE MULLERIAN DUCTS (BY SIMILARITY).
• SUBCELLULAR LOCATION: POSSIBLY SECRETED AND ASSOCIATES WITH THE EXTRACELLULAR MATRIX.
• TISSUE SPECIFICITY: EXPRESSION IS RESTRICTED TO PLACENTA, KIDNEY, TESTIS, UTERUS, FETAL LUNG, AND FETAL AND ADULT BRAIN.
• SIMILARITY: BELONGS TO THE WNT FAMILY.
• FUNCTION: PROBABLE DEVELOPMENTAL PROTEIN. SIGNALING BY WNT-7A ALLOWS SEXUALLY DIMORPHIC DEVELOPMENT OF THE MULLERIAN DUCTS.
• SUBCELLULAR LOCATION: POSSIBLY SECRETED AND ASSOCIATES WITH THE EXTRACELLULAR MATRIX.
• DISEASE: MALE MICE LACKING WNT-7A FAIL TO UNDERGO REGRESSION OF THE MULLERIAN DUCT AS A RESULT OF THE ABSENCE OF THE RECEPTOR FOR MULLERIAN-INHIBITING SUBSTANCE. WNT7A-DEFICIENT FEMALES ARE INFERTILE BECAUSE OF ABNORMAL DEVELOPMENT OF THE OVIDUCT AND UTERUS, BOTH OF WHICH ARE MULLERIAN DUCT DERIVATIVES.
• SIMILARITY: BELONGS TO THE WNT FAMILY.

(data from Expasy)

Online Mendelian Inheritance in Man

"The OMIM database was initiated in the early 1960s by Dr. Victor A. McKusick as a catalog of mendelian traits and disorders, entitled Mendelian Inheritance in Man (MIM). Twelve book editions of MIM were published between 1966 and 1998. The online version, OMIM, was created in 1985 by a collaboration between the National Library of Medicine and the William H. Welch Medical Library at Johns Hopkins."

• WINGLESS-TYPE MMTV INTEGRATION SITE FAMILY, MEMBER 3A; WNT3A
• WINGLESS-TYPE MMTV INTEGRATION SITE FAMILY, MEMBER 7A; WNT7A
• CATENIN, BETA-1; CTNNB1

References

Links: Online Textbooks | Search Textbooks | PubMed | Search PubMed | Glossary

Online Textbooks

Molecular Biology of the Cell (4th Edn) Alberts, Bruce; Johnson, Alexander; Lewis, Julian; Raff, Martin; Roberts, Keith; Walter, Peter. New York: Garland Publishing; 2002.

Developmental Biology (6th Edn) Gilbert, Scott F. Sunderland (MA): Sinauer Associates, Inc.; c2000.

Search NLM Online Textbooks- "hox" : Molecular Biology of the Cell | Molecular Cell Biology | The Cell- A molecular Approach

PubMed

Reviews

• Tadros W, Lipshitz HD. Setting the stage for development: mRNA translation and stability during oocyte maturation and egg activation in Drosophila. Dev Dyn. 2005 Mar;232(3):593-608.

Articles

Search PubMed

Search Aug2005 "Wnt" ?? reference articles of which ?? were reviews.

Search PubMed: term= Wnt

Glossary

A | B | C | D | E | F | G | H | I | J | K | L | M | N | O | P | Q | R | S | T | U | V | W | X | Y | Z | Numbers

External Links

The nature of the internet is that some links may change over time. If the link no longer functions, search the internet using the link term.

The Wnt gene Homepage by Roel Nusse

• Atlas of Genetics and Cytogenetics in Oncology and Haematology - The WNT Signaling Pathway and Its Role in Human Solid Tumors
• Mouse Wnt genes
• Comparative table of all vertebrate Wnt genes
• alignments of all mammalian Wnt genes
• Other Wnt pages

Quick Links

Development Notes ----------------- Menstrual Cycle Week 1 Week 2 Week 3 Week 4 Placenta Serial Images Genes/DNA Molecular Dev Abnormal Dev Postnatal Dev Notes Index

System Notes ----------------- Heart/Cardiovascular Respiratory Coelomic cavity Gastrointestinal Tract Head and Neck Neural Neural Crest Eye Ear Nose Endocrine Urogenital Musculoskeletal Integumentary

Movies ----------------- Embryo Growth Ultrasound Week 1 Week 2 Week 3 Week 4 Stage 13/14 Stage 22 Neural Head and Neck Heart Vasculature Gastrointestinal Urogenital Other Embryos Larsen Internet

Other Embryos ----------------- Chicken Fly Frog Mouse Rabbit Rat Worm Zebrafish Guinea Pig

UNSW Embryology ISBN: 978 0 7334 2609 4

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