Analysis of the vestigial tail mutation demonstrates that Wnt-3a gene dosage regulates mouse axial development.

Greco, Tamara L.; Takada, Shinji; Newhouse, Matthew M.; McMahon, Jill A.; McMahon, Andrew P.; Camper, Sally A.

doi:10.1101/gad.10.3.313

Cited by 234 publications

(170 citation statements)

References 45 publications

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“…Animals heterozygous for null alleles of either Wnt3a or T display kinked or shortened tail phenotypes due to haploinsufficiency (Dobrovolskaia-Zavadskaia 1927;Greco et al 1996). Examination of ordered allelic series of mutations in either Wnt3a or T demonstrates a correlation between the severity of the axial truncation and gene dosage (MacMurray and Shin 1988;Greco et al 1996) and suggests that Brachyury and Wnt3a participate in the development of the entire A-P axis. Our demonstration that T is a transcriptional target of the Wnt3a signaling pathway is consistent with this genetic data and suggest that a primary function of Wnt3a may be to tightly regulate the dosage of T during embryogenesis.…”

Section: Resultsmentioning

confidence: 99%

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T (Brachyury) is a direct target of Wnt3a during paraxial mesoderm specification

Yamaguchi

Takada²,

Yoshikawa³

et al. 1999

Genes & Development

479

410

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Wnt3a encodes a signal that is expressed in the primitive streak of the gastrulating mouse embryo and is required for paraxial mesoderm development. In its absence cells adopt ectopic neural fates. Embryos lacking the T-boxcontaining transcription factors, Brachyury or Tbx6, also lack paraxial mesoderm. Here we show that Brachyury is specifically down-regulated in Wnt3a mutants in cells fated to form paraxial mesoderm. Transgenic analysis of the T promoter identifies T (Brachyury) as a direct transcriptional target of the Wnt signaling pathway. Our results suggest that Wnt3a, signaling via Brachyury, modulates a balance between mesodermal and neural cell fates during gastrulation. Received September 13, 1999; revised version accepted October 13, 1999. The embryonic mesoderm of the mammalian embryo is formed by a series of inductive interactions first in the primitive streak, which gives rise to head and trunk mesoderm, and later in the tailbud, which generates the most posterior mesoderm of the tail. As development progresses, successively posterior structures are generated, leading to a posterior extension of the body axis. Previous studies have established that Wnt3a, which encodes a member of the Wnt family of secreted signaling molecules (for review, see Cadigan and Nusse 1997;Moon et al. 1997), is expressed in pluripotent ectoderm cells of the primitive streak during gastrulation (Takada et al. 1994). At early somite stages [8.0-8.5 days postcoitum (dpc)], the Wnt3a expression domain correlates with a domain of cells in the anterior primitive streak fated to give rise to paraxial mesoderm (for review, see Tam and Trainor 1994;Wilson and Beddington 1996). Moreover, the anterior and lateral limits of the Wnt3a expression domain lie between cells fated to give rise to paraxial mesoderm and cells that will give rise to neural ectoderm.A requirement for Wnt3a in the specification of trunk and tail paraxial somitic mesoderm fates has been demonstrated by mutant analyses. Wnt3a homozygous null mutant embryos lack all but the anterior-most seven to nine somites (Takada et al. 1994;Greco et al. 1996;Yoshikawa et al. 1997). As a consequence, only the most rostral cervical vertebrae are formed. Histological and molecular analyses demonstrate that ectopic neural structures form in place of posterior paraxial mesoderm (Yoshikawa et al. 1997 Mesoderm specification is thought to be regulated, at least in part, by members of the T-box gene family of DNA-binding transcription factors (Smith 1999). Two of these, T and Tbx6, are coexpressed with Wnt3a in the primitive streak during gastrulation (Takada et al. 1994;Chapman et al. 1996). Mutations in either gene lead to a loss of trunk and tail mesoderm (Chesley 1935;Chapman and Papaioannou 1998). Ectopic neural tubes form in place of paraxial mesoderm in the Tbx6 mutants, but it is not clear how similar the neural tube abnormalities noted in the T homozygotes are to the Wnt3a phenotype. Given the similarities between the Wnt3a and T-box mutant phenotypes, we have investiga...

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Section: Resultsmentioning

confidence: 99%

“…Wnt3a homozygous null mutant embryos lack all but the anterior-most seven to nine somites (Takada et al 1994;Greco et al 1996;Yoshikawa et al 1997). As a consequence, only the most rostral cervical vertebrae are formed.…”

mentioning

confidence: 99%

T (Brachyury) is a direct target of Wnt3a during paraxial mesoderm specification

Yamaguchi

Takada²,

Yoshikawa³

et al. 1999

Genes & Development

479

410

View full text Add to dashboard Cite

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“…The Wnt signaling pathway was known to be important in the development and patterning of the skeleton since the early-mid 1990s when studies demonstrated that Wnt-3a mutations resulted in altered mouse axial development (42). A few years later it was shown that the lowdensity lipoprotein receptor-related protein 6 (Lrp6) knockout (Lrp6 -/-) mouse had developmental abnormalities that phenocopied many of the defects observed in mice carrying mutations in Wnt-3a, Wnt-1 or Wnt-7a genes (97).…”

Section: Role Of the Wnt Pathway In Bone Cell Functionmentioning

confidence: 99%

Osteocytes, mechanosensing and Wnt signaling

Bonewald¹,

Johnson²

2008

Bone

918

760

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The majority of bone cell biology focuses on activity on the surface of the bone with little attention paid to the activity that occurs below the surface. However, with recent new discoveries, osteocytes, cells embedded within the mineralized matrix of bone, are becoming the target of intensive investigation. In this article, the distinctions between osteoblasts and their descendants, osteocytes, are reviewed. Osteoblasts are defined as cells that make bone matrix and osteocytes are thought to translate mechanical loading into biochemical signals that affect bone (re)modeling. Osteoblasts and osteocytes should have similarities as would be expected of cells of the same lineage, yet these cells also have distinct differences, particularly in their responses to mechanical loading and utilization of the various biochemical pathways to accomplish their respective functions. For example, the Wnt/ β-catenin signaling pathway is now recognized as an important regulator of bone mass and bone cell functions. This pathway is important in osteoblasts for differentiation, proliferation and the synthesis bone matrix, whereas osteocytes appear to use the Wnt/β-catenin pathway to transmit signals of mechanical loading to cells on the bone surface. New emerging evidence suggests that the Wnt/β-catenin pathway in osteocytes may be triggered by crosstalk with the prostaglandin pathway in response to loading which then leads to a decrease in expression of negative regulators of the pathway such as Sost and Dkk1. The study of osteocyte biology is becoming an intense area of research interest and this review will examine some of the recent findings that are reshaping our understanding of bone/bone cell biology. KeywordsOsteocytes; bone; Wnt/β-catenin signaling; Mechanosensation; Mechanical loading Osteocytes compose over 90-95% of all bone cells in the adult skeleton and are thought to respond to mechanical strain to send signals of resorption or formation (70). Osteocytes are usually regularly dispersed throughout the mineralized matrix especially in cortical bone. These cells are connected to each other and cells on the bone surface through dendritic processes that occupy tiny canals called canaliculi (For review see (17)). Not only do these cells communicate with each other and with cells on the bone surface but their dendritic processes are in contact with the bone marrow (59) giving them the potential to recruit osteoclast precursors to stimulate bone resorption (133)(12) and to regulate mesenchymal stem cell differentiation (48).

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“…In the vestigial tail (vt) mouse mutant, a hypomorph of Wnt3a, caudal somites are missing (Greco et al, 1996), and oscillating expression of the Wnt target Axin2 is lost (Aulehla et al, 2003). The phenotype of Lrp6 null mutant mice with loss of caudal somites is very similar (Pinson et al, 2000).…”

Section: Dkk1 and Vertebral Developmentmentioning

confidence: 99%