Pleiotropic and diverse expression of ZFHX1B gene transcripts during mouse and human development supports the various clinical manifestations of the “Mowat–Wilson” syndrome

Bassez, Guillaume; Camand, Olivier; Cacheux, Valère; Kobetz, Alexandra; Moal, Florence Dastot-Le; Marchant, Dominique; Catala, Martin; Abitbol, Marc; Goossens, Michel

doi:10.1016/j.nbd.2003.10.004

Cited by 50 publications

(51 citation statements)

References 33 publications

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“…Moreover, Western blotting revealed protein bands other than the expected 190 kDa size of SIP1 protein. In fact, a comprehensive analysis through human and mouse tissues revealed multiple transcripts of SIP1 in both species (Bassez et al, 2004). Taken together with the immunofluorescence data, these results suggest that SIP1 protein expression is tightly regulated, and may also indicate the existence of alternative SIP1 transcripts.…”

Section: Discussionmentioning

confidence: 53%

Novel monoclonal antibodies detect Smad-interacting protein 1 (SIP1) in the cytoplasm of human cells from multiple tumor tissue arrays

Öztaş

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Özcan

et al. 2010

Experimental and Molecular Pathology

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Smad-interacting protein 1 (SIP1, also known as ZEB2) represses the transcription of E-cadherin and mediates epithelial-mesenchymal transition in development and tumor metastasis. Due to the lack of human SIP1-specific antibodies, its expression in human tumor tissues has not been studied in detail by immunohistochemistry. Hence, we generated two anti-SIP1 monoclonal antibodies, clones 1C6 and 6E5, with IgG1 and IgG2a isotypes, respectively. The specificity of these antibodies was shown by Western blotting studies using siRNA mediated downregulation of SIP1 and ZEB1 in a human osteosarcoma cell line. In the same context, we also compared them with 5 commercially available SIP1 antibodies. Antibody specificity was further verified in an inducible cell line system by immunofluorescence. By using both antibodies, we evaluated the tissue expression of SIP1 in paraffin-embedded tissue microarrays consisting of 22 normal and 101 tumoral tissues of kidney, colon, stomach, lung, esophagus, uterus, rectum, breast and liver. Interestingly, SIP1 predominantly displayed a cytoplasmic expression, while the nuclear localization of SIP1 was observed in only 6 cases. Strong expression of SIP1 was found in distal tubules of kidney, glandular epithelial cells of stomach and hepatocytes, implicating a co-expression of SIP1 and E-cadherin. Squamous epithelium of the esophagus and surface epithelium of colon and rectum were stained with moderate to weak intensity. Normal uterus, breast and lung tissues remained completely negative. By comparison with their normal tissues, we observed SIP1 overexpression in cancers of the kidney, breast, lung and uterus. However, SIP1 expression was found to be downregulated in tumors from colon, rectum, esophagus, liver and stomach tissues. Finally we did nuclear/cytoplasmic fractionation in 3 carcinoma cell lines and detected SIP1 in both fractions, nucleus being the dominant one. To our best knowledge, this is the first comprehensive immunohistochemical study of the expression of SIP1 in a series of human cancers. Our finding that SIP1 is not exclusively localized to nucleus suggests that the subcellular localization of SIP1 is regulated in normal and tumor tissues. These novel monoclonal antibodies may help elucidate the role of SIP1 in tumor development.

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Section: Discussionmentioning

confidence: 53%

Novel monoclonal antibodies detect Smad-interacting protein 1 (SIP1) in the cytoplasm of human cells from multiple tumor tissue arrays

Öztaş

Avci

Özcan

et al. 2010

Experimental and Molecular Pathology

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“…Furthermore, our marker analysis indicated that, in addition to its presence in spinal neural progenitors (Bassez et al, 2004;Miyoshi et al, 2006), Sip1 (Smad-interacting protein 1; also known as Zfhx1b or Zeb2) is detected in visceral MNs. Sip1 is a member of the Zfhx1 family of two-handed zinc-finger/homeodomain proteins (van Grunsven et al, 2001;Bassez et al, 2004;Seuntjens et al, 2009). It was detected in prospective visceral MNs containing Foxp1 (Fig.…”

Section: Oc Factors Control the Ratio Between Somatic And Visceral Mnsmentioning

confidence: 89%

Onecut transcription factors act upstream of Isl1 to regulate spinal motoneuron diversification

et al. 2012

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SUMMARYDuring development, spinal motoneurons (MNs) diversify into a variety of subtypes that are specifically dedicated to the motor control of particular sets of skeletal muscles or visceral organs. MN diversification depends on the coordinated action of several transcriptional regulators including the LIM-HD factor Isl1, which is crucial for MN survival and fate determination. However, how these regulators cooperate to establish each MN subtype remains poorly understood. Here, using phenotypic analyses of single or compound mutant mouse embryos combined with gain-of-function experiments in chick embryonic spinal cord, we demonstrate that the transcriptional activators of the Onecut family critically regulate MN subtype diversification during spinal cord development. We provide evidence that Onecut factors directly stimulate Isl1 expression in specific MN subtypes and are therefore required to maintain Isl1 production at the time of MN diversification. In the absence of Onecut factors, we observed major alterations in MN fate decision characterized by the conversion of somatic to visceral MNs at the thoracic levels of the spinal cord and of medial to lateral MNs in the motor columns that innervate the limbs. Furthermore, we identify Sip1 (Zeb2) as a novel developmental regulator of visceral MN differentiation. Taken together, these data elucidate a comprehensive model wherein Onecut factors control multiple aspects of MN subtype diversification. They also shed light on the late roles of Isl1 in MN fate decision.

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“…The Zfhx1b gene (44.810557 Mb), which encodes zinc finger homeobox 1b protein, showed the highest expression heritability correlation in the liver (r 5 -0.919, P < 4.99 -39 ), but none in brain. The Zfhxb1 protein is a Smad-interacting transcriptional corepressor involved in Wnt and hedgehog signaling (Bassez et al, 2004;Verstappen et al, 2008;Isohata et al, 2009). Detrimental variants of the gene cause the developmental disorder Mowat-Wilson syndrome, which presents with multiple congenital deficits, including mental retardation (Zweier et al, 2002).…”

Section: Identification Of Candidate Chromosome 2 and 7 Modifier Genesmentioning

confidence: 99%

Peripheral reduction of β-amyloid is sufficient to reduce brain β-amyloid: Implications for Alzheimer's disease

et al. 2011

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2ModGene LLC, Cardiff-by-the-Sea, CaliforniaThree loci that modify b-amyloid (Ab) accumulation and deposition in the brains of a mouse model of Alzheimer's disease have been previously described. One encompasses the Psen2 gene encoding presenilin 2, a component of the g-secretase activity responsible for generating Ab by proteolysis. We show that the activity of mouse Psen2, as measured by levels of mRNA accumulation, unexpectedly is heritable in the liver but not the brain, suggesting liver as the origin of brain Ab deposits. Administration of STI571, a cancer therapeutic that does not cross the blood-brain barrier, reduced accumulation of Ab in both the blood and the brain, confirming brain Ab's peripheral origin and suggesting that STI571 and related compounds might have therapeutic/prophylactic value in human Alzheimer's disease. The genes Cib1 and Zfhx1b reside within the other modifier loci and also exhibit heritable expression in the liver, suggesting that they too contribute to Ab accumulation. V V C 2011 Wiley-Liss, Inc.

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Pleiotropic and diverse expression of ZFHX1B gene transcripts during mouse and human development supports the various clinical manifestations of the “Mowat–Wilson” syndrome

Cited by 50 publications

References 33 publications

Novel monoclonal antibodies detect Smad-interacting protein 1 (SIP1) in the cytoplasm of human cells from multiple tumor tissue arrays

Novel monoclonal antibodies detect Smad-interacting protein 1 (SIP1) in the cytoplasm of human cells from multiple tumor tissue arrays

Onecut transcription factors act upstream of Isl1 to regulate spinal motoneuron diversification

Peripheral reduction of β-amyloid is sufficient to reduce brain β-amyloid: Implications for Alzheimer's disease

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