Lef1 expression is activated by BMP-4 and regulates inductive tissue interactions in tooth and hair development.

Kratochwil, Klaus; Dull, Maude; Fariñas, Isabel; Galceran, Juan; Grosschedl, Rudolf

doi:10.1101/gad.10.11.1382

Cited by 395 publications

(347 citation statements)

References 49 publications

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“…In large part, this regulation is achieved at the level of gene transcription, and in recent years, several signaling pathways and transcription factors important for epithelial morphogenesis have been described. These include pathways involving Wnt ligands, ␤-catenin and Lef/Tcf transcription factors (Zhou et al, 1995;Kratochwil et al, 1996;Gat et al, 1998;DasGupta and Fuchs, 1999;Huelsken et al, 2001;Merrill et al, 2001), as well as Shh ligands, and patched and Gli transcription factors (Bitgood and McMahon, 1995;Oro et al, 1997;StJacques et al, 1998;Chiang et al, 1999;Wang et al, 2000). Of interest, the developmental roles of these pathways are conserved from Drosophila to mammals, suggesting the possibility that the function of other regulators involved in developmental control of epidermis in Drosophila may be conserved in mammals (Oro and Scott, 1998;Fuchs et al, 2001).…”

Section: Discussionmentioning

confidence: 99%

Identification and characterization of Grainyhead‐like epithelial transactivator (GET‐1), a novel mammalian Grainyhead‐like factor

Kudryavtseva¹,

Sugihara²,

Wang³

et al. 2003

Developmental Dynamics

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LMO-4 is an LIM-only factor that is highly expressed in many epithelial cells, including those of the epidermis and hair follicles. Because LMOs may function by interacting with DNA-binding proteins, we have used the yeast two-hybrid system to screen mouse skin libraries for LMO-4 -interacting DNA-binding proteins. In this screen, we isolated a novel LMO-4 -interacting factor highly related to the Drosophila gene Grainyhead. Grainyhead is epidermally expressed and carries out important functions in cuticular formation in the fly embryo. With the identification of this novel mammalian Grainyhead-like gene, referred to as Grainyhead-like epithelial transactivator 1 (GET-1), the known members of the mammalian Grainyhead-like gene family are extended to six, falling into two classes based on sequence homology. Of interest, the expression pattern of GET-1 is similar to that of Drosophila Grainyhead with highest expression in the somatic ectoderm/epidermis, but GET-1 is additionally expressed in epithelial cells of gastrointestinal, genitourinary, and respiratory tracks. The GET-1 protein localizes to the nucleus and binds to at least one Grainyhead DNA-binding site. The GET-1 DNA-binding domain maps to a region containing homology to the Drosophila Grainyhead DNA-binding domain. GET-1 homodimerizes in solution by means of a short C-terminally located domain that is homologous to other Grainyhead-like genes. A short domain located between amino acids 100 and 190, which bears no homology to known transactivation domains, is sufficient to confer transactivation to the heterologous GAL4 DNA-binding domain. In addition, GET-1 appears to contain repression domains consistent with the observation that Grainyhead and other mammalian Grainyhead-like genes can act both as activators and repressors. These data suggest that GET-1 is a transcriptional regulator that may perform important functions in epithelial tissues of mammals. Developmental Dynamics 226:604 -617, 2003.

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Section: Discussionmentioning

confidence: 99%

Identification and characterization of Grainyhead‐like epithelial transactivator (GET‐1), a novel mammalian Grainyhead‐like factor

Kudryavtseva¹,

Sugihara²,

Wang³

et al. 2003

Developmental Dynamics

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“…The protein product of this gene is a transcription factor that plays a role in activating Wnt target genes and it is also a critical factor affecting the survival of the epithelial cells during tooth morphogenesis (Sasaki et al 2005). Mice homozygous for the Lef1 deletion died shortly after birth and showed abnormalities in epithelial-mesenchymal interactions, which led to an arrest of tooth development at the bud stage (Kratochwil et al 1996). Defects in odontogenesis were also observed in mice overexpressing Wnt-signaling inhibitors, including Dickkopf and secreted frizzled-related protein 3 (Sarkar and Sharpe 2000;Andl et al 2002).…”

Section: Resultsmentioning

confidence: 99%

Axis inhibition protein 2 (AXIN2) polymorphisms may be a risk factor for selective tooth agenesis

2006

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Selective tooth agenesis is the most common developmental abnormality of the human dentition. To date, this abnormality has been associated only with mutations in MSX1 and PAX9 mutations, however it has recently been suggested that mutations of axis inhibition protein 2 (AXIN2) may also contribute to this complex anomaly. The protein product of this gene is a negative regulator of the Wnt-signaling pathway. We searched for AXIN2 variants in a group of patients with tooth agenesis who did not have mutations of MSX1 and PAX9. Using multi-temperature single-stranded conformational polymorphism and sequencing analysis, we identified three novel AXIN2 gene variants: c.956+16A>G, c.1060-17C>T and c.2062C>T. We also observed that individuals carrying the c.956+16G and c.2062T alleles exhibited an increased risk of tooth agenesis. The calculated odds ratio was 2.94 (95% CI 1.104-7.816; p=0.026; p corr =0.234) and 4.01 (95% CI 1.563-10.301; p=0.002; p corr =0.018), respectively. Moreover, we found that the c.2062C>T transition may change exon splice enhancer-specific binding sites of the protein splicing regulators SC35 and SF2/ASF. This alternation may negatively affect the splicing process and cellular concentration of AXIN2 protein. Our findings suggest that AXIN2 polymorphic variants may be associated with both hypodontia and oligodontia.

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“…We show here that expression of Lef1 in the MT hair follicles was reduced, suggesting that Smad4 signaling is required for maintaining expression of this gene in the hair shaft progenitor cells. Previous investigations indicated that Lef1 plays an essential role for hair follicle morphogenesis and targeted disruption of Lef1 blocked hair formation (Kratochwil et al, 1996;DasGupta and Fuchs, 1999). We found that, at the end of the first cycle, Smad4 Co/Co MMTV-Cre hair follicle did not contain matrix and precortex cells, leading to the absence of the hair shaft and the IRS in the MT hair follicles.…”

Section: Discussionmentioning

confidence: 99%

“…Thus, the Smad4-deficient hair follicles were missing the hair shaft, the IRS and the cortical and medulla cells. We then determined expression of Lef1, an HMG box transcription factor that is Smad4 deficiency results in skin tumor formation W Qiao et al expressed in the hair matrix and the precursor cells of the hair shaft (Figure 4a), and is essential for hair growth (Kratochwil et al, 1996;DasGupta and Fuchs, 1999). In MT mice, we found that Lef1 staining was negative, suggesting the lack of such progenitors in the MT hair follicles (Figure 4b).…”

Section: Smad4-deficient Hair Follicles Did Not Exhibit Normal Differmentioning

confidence: 99%

Hair follicle defects and squamous cell carcinoma formation in Smad4 conditional knockout mouse skin

et al. 2005

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Smad4 is the common mediator for TGFb signals, which play important functions in many biological processes. To study the role of Smad4 in skin development and epidermal tumorigenesis, we disrupted this gene in skin using the Cre-loxP approach. We showed that absence of Smad4 blocked hair follicle differentiation and cycling, leading to a progressive hair loss of mutant (MT) mice. MT hair follicles exhibited diminished expression of Lef1, and increased proliferative cells in the outer root sheath. Additionally, the skin of MT mice exhibited increased proliferation of basal keratinocytes and epidermal hyperplasia. Furthermore, we provide evidence that the absence of Smad4 resulted in a block of both TGFb and bone morphogenetic protein (BMP) signaling pathways, including p21, a well-known cyclin-dependent kinase inhibitor. Consequently, all MT mice developed spontaneous malignant skin tumors from 3 months to 13 months of age. The majority of tumors are malignant squamous cell carcinomas. A most notable finding is that tumorigenesis is accompanied by inactivation of phosphatase and tensin homolog deleted on chromosome 10 (Pten), activation of AKT, fast proliferation and nuclear accumulation of cyclin D1. These observations revealed the essential functions of Smad4-mediated signals in repressing skin tumor formation through the TGFb/BMP pathway, which interacts with the Pten signaling pathway.

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Lef1 expression is activated by BMP-4 and regulates inductive tissue interactions in tooth and hair development.

Cited by 395 publications

References 49 publications

Identification and characterization of Grainyhead‐like epithelial transactivator (GET‐1), a novel mammalian Grainyhead‐like factor

Identification and characterization of Grainyhead‐like epithelial transactivator (GET‐1), a novel mammalian Grainyhead‐like factor

Axis inhibition protein 2 (AXIN2) polymorphisms may be a risk factor for selective tooth agenesis

Hair follicle defects and squamous cell carcinoma formation in Smad4 conditional knockout mouse skin

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