The LIM domain-only protein LMO4 is required for neural tube closure

Lee, Soo Kyung; Jurata, Linda W.; Nowak, Roberta B.; Lettieri, Karen; Kenny, Daryn A.; Pfaff, Samuel L.; Gill, Gordon N.

doi:10.1016/j.mcn.2004.04.010

Cited by 56 publications

(66 citation statements)

References 44 publications

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“…Deletion of LMO4 causes decreased proliferation of mammary epithelial cells and impaired lobuloalveolar development LMO4 knockout mice die during embryogenesis or at birth (Hahm et al, 2004;Lee et al, 2005;Sum et al, 2005c), precluding their use for studying the role of LMO4 in postnatal mammary gland development. We therefore interbred floxed LMO4 mice (Lee et al, 2005) with whey acidic protein (WAP)-Cre (Wagner et al, 1997) and mouse mammary tumor virus (MMTV)-Cre (Wagner et al, 1997) transgenic mice to achieve two types of Cre recombinase-mediated deletion of the LMO4 gene within mammary glands of mice (Supplementary Figure S1).…”

Section: Resultsmentioning

confidence: 99%

“…We therefore interbred floxed LMO4 mice (Lee et al, 2005) with whey acidic protein (WAP)-Cre (Wagner et al, 1997) and mouse mammary tumor virus (MMTV)-Cre (Wagner et al, 1997) transgenic mice to achieve two types of Cre recombinase-mediated deletion of the LMO4 gene within mammary glands of mice (Supplementary Figure S1). Whole-mount and histological analyses were used to study the effect of LMO4 deletion on mammary gland development.…”

Section: Resultsmentioning

confidence: 99%

“…LMO4 fl/fl mice on the C57/BL6 background were described previously (Lee et al, 2005). We generated mice carrying mammary gland LMO4 knockouts by mating the WAP-Cre and MMTV-Cre mice with LMO4 fl/fl mice.…”

Section: Methodsmentioning

confidence: 99%

“…We used published PCR primer sequences for identifying MMTV-Cre and WAP-Cre mice according to instructions from the Jackson Laboratory. PCR primers for detecting wild type, floxed and deleted LMO4 alleles are published previously (Lee et al, 2005).…”

Section: Methodsmentioning

confidence: 99%

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The LIM-only factor LMO4 regulates expression of the BMP7 gene through an HDAC2-dependent mechanism, and controls cell proliferation and apoptosis of mammary epithelial cells

Wang

Lin

et al. 2007

Oncogene

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The nuclear LIM-only protein 4 (LMO4) is upregulated in breast cancer, especially estrogen receptor-negative tumors, and its overexpression in mice leads to hyperplasia and tumor formation. Here, we show that deletion of LMO4 in the mammary glands of mice leads to impaired lobuloalveolar development due to decreased epithelial cell proliferation. With the goal of discovering potential LMO4-target genes, we also developed a conditional expression system in MCF-7 cells for both LMO4 and a dominant negative (DN) form of its co-regulator, cofactor of LIM domains (Clim/Ldb/Nli). We then used DNA microarrays to identify genes responsive to LMO4 and DN-Clim upregulation. One of the genes common to both data sets was bone morphogenic protein 7 (BMP7), whose expression is also significantly correlated with LMO4 transcript levels in a large dataset of human breast cancers, suggesting that BMP7 is a bona fide target gene of LMO4 in breast cancer. Inhibition of BMP7 partially blocks the effects of LMO4 on apoptosis, indicating that BMP7 mediates at least some functions of LMO4. Gene transfer studies show that LMO4 regulates the BMP7 promoter, and chromatin immunoprecipitation studies show that LMO4 and its cofactor Clim2 are recruited to the BMP7 promoter. Furthermore, we demonstrate that HDAC2 recruitment to the BMP7 promoter is inhibited by upregulation of LMO4 and that HDAC2 knockdown upregulates the promoter. These studies suggest a novel mechanism of action for LMO4: LMO4, Clim2 and HDAC2 are part of a transcriptional complex, and increased LMO4 levels can disrupt the complex, leading to decreased HDAC2 recruitment and increased promoter activity.

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Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

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The LIM-only factor LMO4 regulates expression of the BMP7 gene through an HDAC2-dependent mechanism, and controls cell proliferation and apoptosis of mammary epithelial cells

Wang

Lin

et al. 2007

Oncogene

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“…The four LMOs play roles in mammalian development (Yamada et al, 1998;Hahm et al, 2004;Tse et al, 2004;Lee et al, 2005). In addition, LMO1 and LMO2 act as oncogenes in acute lymphoblastic leukemia (Rabbitts, 1998), and recent studies have defined LMO3 as an oncogene in neuroblastoma (Aoyama et al, 2005) and LMO4 as a protumorigenic factor in breast cancer (Visvader et al, 2001;Sum et al, 2005b).…”

Section: Introductionmentioning

confidence: 99%

LMO4 can interact with Smad proteins and modulate transforming growth factor-β signaling in epithelial cells

Lam

Wang

et al. 2006

Oncogene

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LIM-only protein 4 (LMO4) plays critical roles in mammalian development, and has been proposed to play roles in epithelial oncogenesis, including breast cancer. As LMO4 is highly expressed in the epithelial compartments at locations of active mesenchymal-epithelial interactions, we reasoned that LMO4 might act by modulating signaling pathways involved in mesenchymal-epithelial signaling. One such candidate signal is the transforming growth factor-b (TGFb) cytokine pathway, which plays important roles both in development and cancer. We show here that the transcriptional response to TGFb in epithelial cells is sensitive to LMO4 levels; both up-and downregulation of LMO4 can enhance TGFb signaling as assessed by a TGFb-responsive reporter gene. Furthermore, LMO4 can interact with the MH1 and linker domains of receptor-mediated Smad proteins, and associate with the endogenous TGFb-responsive Plasminogen Activator Inhibitor-1 gene promoter in a TGFb-dependent manner, suggesting that such interactions may mediate the effects of LMO4 on TGFb signaling. When introduced into mammary epithelial cells, LMO4 potentiated the growth-inhibitory effects of TGFb in those cells. These results define a new function for LMO4 as a coactivator in TGFb signaling, and provide a potential novel mechanism for LMO4-mediated regulation in development and oncogenesis.

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Mouse mutants with neural tube closure defects and their role in understanding human neural tube defects

Harris

Juriloff

2006

Birth Defects Research

280

325

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BACKGROUND:The number of mouse mutants and strains with neural tube closure defects (NTDs) now exceeds 190, including 155 involving known genes, 33 with unidentified genes, and eight ''multifactorial'' strains. METHODS: The emerging patterns of mouse NTDs are considered in relation to the unknown genetics of the common human NTDs, anencephaly, and spina bifida aperta. RESULTS: Of the 150 mouse mutants that survive past midgestation, 20% have risk of either exencephaly and spina bifida aperta or both, parallel to the majority of human NTDs, whereas 70% have only exencephaly, 5% have only spina bifida, and 5% have craniorachischisis. The primary defect in most mouse NTDs is failure of neural fold elevation. Most null mutations (>90%) produce syndromes of multiple affected structures with high penetrance in homozygotes, whereas the ''multifactorial'' strains and several null-mutant heterozygotes and mutants with partial gene function (hypomorphs) have low-penetrance nonsyndromic NTDs, like the majority of human NTDs. The normal functions of the mutated genes are diverse, with clusters in pathways of actin function, apoptosis, and chromatin methylation and structure. The female excess observed in human anencephaly is found in all mouse exencephaly mutants for which gender has been studied. Maternal agents, including folate, methionine, inositol, or alternative commercial diets, have specific preventative effects in eight mutants and strains. CONCLUSIONS: If the human homologs of the mouse NTD mutants contribute to risk of common human NTDs, it seems likely to be in multifactorial combinations of hypomorphs and low-penetrance heterozygotes, as exemplified by mouse digenic mutants and the oligogenic SELH/Bc strain.

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The LIM domain-only protein LMO4 is required for neural tube closure

Cited by 56 publications

References 44 publications

The LIM-only factor LMO4 regulates expression of the BMP7 gene through an HDAC2-dependent mechanism, and controls cell proliferation and apoptosis of mammary epithelial cells

The LIM-only factor LMO4 regulates expression of the BMP7 gene through an HDAC2-dependent mechanism, and controls cell proliferation and apoptosis of mammary epithelial cells

LMO4 can interact with Smad proteins and modulate transforming growth factor-β signaling in epithelial cells

Mouse mutants with neural tube closure defects and their role in understanding human neural tube defects

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