Crooked tail (
            <i>Cd</i>
            ) model of human folate-responsive neural tube defects is mutated in Wnt coreceptor lipoprotein receptor-related protein 6

Carter, Michelle; Chen, Xu; Slowinska, Bozena; Minnerath, Sharon R.; Glickstein, Sara B.; Shi, Lei; Campagne, Fabien; Weinstein, Harel; Ross, M. Elizabeth

doi:10.1073/pnas.0501963102

Cited by 92 publications

(92 citation statements)

References 43 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Somite defects are also observed in Crooked tail (Cd) a hypomorphic Lrp6 mutant. Lrp6 Cd is a gain of function mutant, which still can interact with Wnts, but which is unable to respond to Dkk1 and is hyperactive (Carter et al, 2005). Taken together, these results suggest a role of Dkk1 as a negative feedback regulator in the Wnt-Notch oscillator.…”

Section: Dkk1 and Vertebral Developmentmentioning

confidence: 82%

Function and biological roles of the Dickkopf family of Wnt modulators

2006

View full text Add to dashboard Cite

Section: Dkk1 and Vertebral Developmentmentioning

confidence: 82%

Function and biological roles of the Dickkopf family of Wnt modulators

2006

View full text Add to dashboard Cite

“…Smurf ubiquitin ligases1 and 2, involved in degradation of the PCP core protein Prickle1, show exencephaly and/or spina bifida as well as inner ear defects in 25% of embryos which lose three of four Smurf alleles (Narimatsu et al, 2009). The crooked tail allele of Lrp6 allele on a mixed DBA/2J x A/J genetic background shows $20-30% exencephalic embryos, and not craniorachischisis or spina bifida (Carter et al, 2005). Although associated with canonical Wnt signaling, Lrp6 is necessary for Xenopus convergent extension (Tahinci , 2007), yet the exencephalic mice are of normal size, similar to Cecr2.…”

Section: Discussionmentioning

confidence: 99%

Role of chromatin remodeling gene Cecr2 in neurulation and inner ear development

Dawe

Kooistra

Fairbridge

et al. 2011

Developmental Dynamics

View full text Add to dashboard Cite

The loss of Cecr2, which encodes a chromatin remodeling protein, has been associated with the neural tube defect (NTD) exencephaly and open eyelids in mice. Here, we show that two independent mutations of Cecr2 are also associated with specific inner ear defects. Homozygous mutant 18.5 days post coitus (dpc) fetuses exhibited smaller cochleae as well as rotational defects of sensory cells and extra cell rows in the inner ear reminiscent of planar cell polarity (PCP) mutants. Cecr2 was expressed in the neuroepithelium, head mesenchyme, and the cochlear floor. Although limited genetic interaction for NTDs was seen with Vangl2, a microarray analysis of PCP genes did not reveal a direct connection to this pathway. The mechanism of Cecr2 action in neurogenesis and inner ear development is likely complex.

show abstract

“…Recently a human LRP6 mutation was reported in a family with coronary artery disease and osteoporosis, further suggesting that loss of function LRP6 mutations result in low bone mass [55]. In contrast, the hypermorphic Crooked tail Lrp6 mouse mutant is caused by a missense mutation that prevents DKK1 mediated Wnt inhibition, though the adult bone phenotype was not examined in the Lrp6 Cd/+ mice [56]. Further studies are required to determine if LRP6 performs the same role as LRP5 in adult bone and if DKK1 inhibits these receptors differentially during osteogenesis.…”

Section: Discussionmentioning

confidence: 99%

Bone mass is inversely proportional to Dkk1 levels in mice

MacDonald

Joiner

Oyserman

et al. 2007

Bone

156

104

View full text Add to dashboard Cite

The Wnt/β-catenin signaling pathway has emerged as a key regulator in bone development and bone homeostasis. Loss-of-function mutations in the Wnt co-receptor LRP5 result in osteoporosis and "activating" mutations in LRP5 result in high bone mass. Dickkopf-1 (DKK1) is a secreted Wnt inhibitor that binds LRP5 and LRP6 during embryonic development, therefore it is expected that a decrease in DKK1 will result in an increase in Wnt activity and a high bone mass phenotype. Dkk1 −/− knockout mice are embryonic lethal, but mice with hypomorphic Dkk1 d (doubleridge) alleles that express low amounts of Dkk1 are viable. In this study we generated an allelic series by crossing Dkk1 +/− and Dkk1 +/d mice resulting in the following genotypes with decreasing Dkk1 expression levels: +/+, +/d, +/− and d/−. Using μCT imaging we scanned dissected left femora and calvariae from eight week old mice (n=60). We analyzed the distal femur to represent trabecular bone and the femur diaphysis for cortical endochondral bone. A region of the parietal bones was used to analyze intramembranous bone of the calvaria. We found that trabecular bone volume is increased in Dkk1 mutant mice in a manner that is inversely proportional to the level of Dkk1 expression. Trabeculae number and thickness were significantly higher in the low Dkk1 expressing genotypes from both female and male mice. Similar results were found in cortical bone with an increase in cortical thickness and cross sectional area of the femur diaphysis that correlated with lower Dkk1 expression. No consistent differences were found in the calvaria measurements. Our results indicate that the progressive Dkk1 reduction increases trabecular and cortical bone mass and that even a 25% reduction in Dkk1 expression could produce significant increases in trabecular bone volume fraction. Thus DKK1 is a negative regulator of normal bone homeostasis in vivo. Our study suggests that manipulation of DKK1 function or expression may have therapeutic significance for the treatment of low bone mass disorders.

show abstract

Crooked tail ( Cd ) model of human folate-responsive neural tube defects is mutated in Wnt coreceptor lipoprotein receptor-related protein 6

Cited by 92 publications

References 43 publications

Function and biological roles of the Dickkopf family of Wnt modulators

Function and biological roles of the Dickkopf family of Wnt modulators

Role of chromatin remodeling gene Cecr2 in neurulation and inner ear development

Bone mass is inversely proportional to Dkk1 levels in mice

Contact Info

Product

Resources

About