A loss-of-function mutation in the CFC domain of TDGF1 is associated with human forebrain defects

Cruz, June M. de la; Bamford, Richard N.; Burdine, Rebecca D.; Roessler, Erich; Barkovich, James; Donnai, Dian; Schier, Alexander F.; Muenke, Maximilian

doi:10.1007/s00439-002-0709-3

Cited by 97 publications

(79 citation statements)

References 21 publications

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“…six2.1 expression in this area is adjacent to the area where wilms tumor 1 (wt1) expression is observed in the intermediate mesoderm. At 24,36, and 48 h after fertilization, strong six2.1 expression is seen in the developing eye and ear consistent with expression patterns in Drosophila and mouse (data not shown).…”

Section: Expression Of Zebrafish Six2 and Bmp4supporting

confidence: 81%

“…A similar approach has been used to confirm that human mutations in CFC1 and TDGF1 result in loss of protein function. 36,37 Human mutations introduced into six2.1 and bmp4 strongly affect the ability of injected RNA to dorsalize or ventralize zebrafish embryos, respectively. At physiologic levels in an embryo, these mutations might have profound effects at multiple steps in kidney development, cumulatively leading to the defects observed in RHD patients.…”

Section: Overexpression Assaymentioning

confidence: 99%

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SIX2 and BMP4 Mutations Associate With Anomalous Kidney Development

Weber

Taylor

Winyard

et al. 2008

Journal of the American Society of Nephrology

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Renal hypodysplasia (RHD) is characterized by reduced kidney size and/or maldevelopment of the renal tissue following abnormal organogenesis. Mutations in renal developmental genes have been identified in a subset of affected individuals. Here, we report the first mutations in BMP4 and SIX2 identified in patients with RHD. We detected 3 BMP4 mutations in 5 RHD patients, and 3 SIX2 mutations in 5 different RHD patients. Overexpression assays in zebrafish demonstrated that these mutations affect the function of Bmp4 and Six2 in vivo. Overexpression of zebrafish six2.1 and bmp4 resulted in dorsalization and ventralization, respectively, suggesting opposing roles in mesendoderm formation. When mutant constructs containing the identified human mutations were overexpressed instead, these effects were attenuated. Morpholino knockdown of bmp4 and six2.1 affected glomerulogenesis, suggesting specific roles for these genes in the formation of the pronephros. In summary, these studies implicate conserved roles for Six2 and Bmp4 in the development of the renal system. Defects in these proteins could affect kidney development at multiple stages, leading to the congenital anomalies observed in patients with RHD.

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Section: Expression Of Zebrafish Six2 and Bmp4supporting

confidence: 81%

Section: Overexpression Assaymentioning

confidence: 99%

SIX2 and BMP4 Mutations Associate With Anomalous Kidney Development

Weber

Taylor

Winyard

et al. 2008

Journal of the American Society of Nephrology

Self Cite

180

138

View full text Add to dashboard Cite

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“…Orthologous genes have been identified in the mouse (Cr-1) (Dono et al, 1993), chicken (Colas and Schoenwolf, 2000), zebrafish (Zhang et al, 1998) and Xenopus (FRL1) (Kinoshita et al, 1995). Related genes include mouse cryptic (Cfc1) and human cryptic (CFC1) (Shen et al, 1997;Bamford et al, 2000;Shen and Schier, 2000;de la Cruz et al, 2002). EGF-CFC family members contain an NH 2 -terminal signal peptide, a modified EGF-like region, a conserved cysteine-rich domain (CFC motif) and a short hydrophobic COOH-terminus that contains additional sequences for glycosylphosphatidylinositol (GPI) cleavage and attachment (Minchiotti et al, 2000) (Figure 1).…”

Section: Identification and Structure Of The Egf-cfc Gene Familymentioning

confidence: 99%

Cripto-1: a multifunctional modulator during embryogenesis and oncogenesis

et al. 2005

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It is increasingly evident that genes known to perform critical roles during early embryogenesis, particularly during stem cell renewal, pluripotentiality and survival, are also expressed during the development of cancer. In this regard, oncogenesis may be considered as the recapitulation of embryogenesis in an inappropriate temporal and spatial manner. The epidermal growth factor-Cripto-1/FRL1/cryptic family of proteins consists of extracellular and cell-associated proteins that have been identified in several vertebrate species. During early embryogenesis, epidermal growth factor-Cripto-1/FRL1/ cryptic proteins perform an obligatory role as coreceptors for the transforming growth factor-beta subfamily of proteins, which includes Nodal. Cripto-1 has also been shown to function as a ligand through a Nodal/Alk4-independent signaling pathway that involves binding to glypican-1 and the subsequent activation through src of phosphoinositol-3 kinase/Akt and ras/mitogen-activated protein kinase intracellular pathways. Expression of Cripto-1 is increased in several human cancers and its overexpression is associated with the development of mammary tumors in mice. Here, we review the role of Cripto-1 during embryogenesis, cell migration, invasion and angiogenesis and how these activities may relate to cellular transformation and tumorigenesis. We also briefly discuss evidence suggesting that Cripto-1 may be involved in stem cell maintenance.

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“…HPE is etiologically heterogeneous, and a number of both environmental and genetic causes have been identified (Muenke and Beachy, 2000;Ming and Muenke, 2002). Mutations in seven genes have been noted to cause human HPE: SHH (Roessler et al, 1996(Roessler et al, , 1997, ZIC2 (Brown et al, 1998), SIX3 (Wallis et al, 1999), TGIF (Gripp et al, 2000), PTCH (Ming et al, 2002b), TDGF1 (De La Cruz et al, 2002), and GLI2 (Roessler et al, 2003). Several other candidate genes for HPE also exist (Kamnasaran et al, 2005).…”

Section: Introductionmentioning

confidence: 99%

TGIF, a gene associated with human brain defects, regulates neuronal development

2006

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-TG-3 -interacting factor (TGIF) is an atypical homeodomain protein.In vitro studies have shown that TGIF can repress transcription mediated by either of two signaling pathways: TGF-␤ and retinoic acid signaling. Mutations in TGIF have been detected in patients with holoprosencephaly (HPE), a severe brain malformation associated with mental retardation. Thus, TGIF must play an essential role in nervous system development. However, the precise function of TGIF during vertebrate neural development is unknown. To investigate the in vivo role of TGIF, we overexpressed TGIF in the developing chick neural tube. Overexpressed TGIF decreased expression of specific genes expressed in dorsally restricted domains of the neural tube, including Cath1, Msx2, Pax6, and Wnt1. In contrast, the expression of other transcription factors, including those necessary for ventral fate such as Nkx2.2, was not affected. Furthermore, a missense mutation in TGIF identified in an HPE patient disrupted the activity of TGIF. In addition, the related protein TGIF2 did not demonstrate the same activity as TGIF. Our data suggest that TGIF plays an important role in regulating the expression of genes expressed in specific dorsal-ventral domains during neural development.

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A loss-of-function mutation in the CFC domain of TDGF1 is associated with human forebrain defects

Cited by 97 publications

References 21 publications

SIX2 and BMP4 Mutations Associate With Anomalous Kidney Development

SIX2 and BMP4 Mutations Associate With Anomalous Kidney Development

Cripto-1: a multifunctional modulator during embryogenesis and oncogenesis

TGIF, a gene associated with human brain defects, regulates neuronal development

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