Vertebrate Frizzleds and interactions with Wnts

Frizzled proteins are seven-transmembrane receptors. There is biochemical and genetic evidence that Frizzleds act as receptors for Wnt proteins, in particular in the case of Frizzled and Dfrizzeld2 interacting with Wingless in Drosophila. Yu et al (2012) have done a systematic survey of each Wnt-Frizzled interaction by co-transfection and Wnt-reporter assays. Wnts can bind the the CRD (cysteine-rich domain) of Frizzled, an extracellular part of the receptor. The CRD domain is found is a multitude of other proteins as well (reviewed by Pej and Grishin 2012).

The structure of the CRD has been solved by Dann (2001) while the structure of the entire human Smoothened (a Frizzled-related receptor) was solved by Wang et al (2013). FRP/FrzB molecules consist of the CRD only and can act as secreted antagonists of Wnt signaling. 

 Little is known about the mechanism of Frizzled signaling. Some but not all Frizzleds stimulate Ca release and PKC activity.

Review: Frizzled Receptors in Development and Diseases Wang et al, 2016. 

Wnt-Frizzled interactionWnt-Frizzled interactions (From Yu et al (2012))

Gene Table



Mutant phenotype


Fzd1 (Fz1)    

Convergent extension defects, with Fzd7 mutant (Yu et al, 2012)

Fzd2-rs1 (Mfz2)    
Fzd2-rs2 (FZD2)    
Fzd3 (Mfz3) stimulate PKC activation Sheldahl 1999Activates b-catenin Umbhauer 2000 Defect in fiber tracts in the rostral CNS (Wang 2002)

Anterior-posterior guidance of commissural axons Lyuksyutova et al, 2003

midbrain morphogenesis defect (with Fz6; Stuebner, 2009)

axonal development in spinal and motor neurons (Hua et al, 2014)

Fzd4 (Mfz4) stimulates PKC activation Sheldahl 1999 Activates b-catenin with Wnt-5A Umbhauer 2000. Becomes internalized after adding Wnt5A (Chen 2003).

Activates Wnt reporter with norrin (Xu, 2004).

Activates Wnt reporter with Wnt5A and LRP5 (Mikels, 2006)

Cerebellar, Auditory, and Esophageal Defects
Wang et al, 2001.
Impaired Corpora Lutea Formation (Hsieh 2005)
Defects in vascular growth, endothelial defects (Ye, 2009)
Kidney phenotype (with Fz8) Ye at al, 2011
Fzd5 (Mfz5)  
Fzd6 (Mfz6) stimulate PKC activation Sheldahl 1999 Hair patterning, tissue polarity (Guo et al, 2004)

midbrain morphogenesis defect (with Fz3; Stuebner, 2009)

Fzd7 (Mfz7) activate siamois and Xnr3 Sheldahl 1999. Activates b-catenin with Wnt-5A, Umbhauer 2000

Tail trunction and kinking (Yu et al, 2012) 

Convergent extension defects, with Fzd2 mutant (Yu et al, 2012)

LTP-mediated synaptic strength, spine growth, and AMPAR localization at synapses (McLeod et al, 2018)

Fzd8 (Mfz8) activate siamois and Xnr3 Sheldahl 1999

Activates Wnt reporter with RSpondin (Nam, 2006)

Kidney phenotype (with Fz4) Ye at al, 2011 
Fzd9 (Mfz9)    B cell development Ranheim 2005

Hippocampal and visuospatial learning defects (Zhao 2005)

Bone loss (Albers et al , 2011) (Heilman et al, 2013)


Smo (smoothened)    arrest at somite stages with a small, linear heart tube, open gut and cyclopia. L/R assymetry phenotype (Zhang 2001)

 human (see also the Human Gene Nomenclature Database for Frizzleds)

 FZD4   Retinal angiogenesis in familial exudative vitreoretinopathy (Robitaille, 2002)
 FZD7   Â Self-renewal HESC (Melchior 2008)
 FZD9 (previously called FZD3)    





recruits XWnt-8 to membrane
Yang-Snyder 1996

activates siamois and Xnr3 Sheldahl 1999

elicits Ca release with Wnt-5A
Slusarski DC, 1997

stimulate PKC activation Sheldahl 1999

Activates beta-catenin (Cong, 2004)


Schematic structure of Frizzled proteins, in comparison to the secreted FRP/FrzB forms.

Frizzled protein structure