The Transcription Factor Atonal homolog 8 Regulates Gata4 and Friend of Gata-2 during Vertebrate Development

Rawnsley, David R.; Xiao, Jiping; Lee, John S.; Liu, Xi; Mericko-Ishizuka, Patricia; Kumar, Vinayak; He, Jie; Basu, Arindam; Lü, Min; Lynn, Francis C.; Pack, Michael; Gasa, Rosa; Kahn, Mark L.

doi:10.1074/jbc.m113.463083

Cited by 32 publications

(41 citation statements)

References 65 publications

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“…It is made available under a The copyright holder for this preprint (which was this version posted May 30, 2019. . https://doi.org/10.1101/655555 doi: bioRxiv preprint lethality [39] to no severe phenotypical alterations in an independently derived loss of function mouse line [40]. A mild phenotype has also been described after pancreas-specific inactivation of a conditional Atoh8 allele [41].…”

Section: Discussionmentioning

confidence: 99%

Atoh8 acts as a regulator of chondrocyte proliferation and differentiation in endochondral bones

Schroeder

Wuelling

Hoffmann

et al. 2019

Preprint

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24 Atonal homolog 8 (Atoh8) is a transcription factor of the basic helix-loop-helix (bHLH) protein 25 family, which is expressed in the cartilaginous elements of endochondral bones. To analyze 26 its function during chondrogenesis we deleted Atoh8 in mice using a chondrocyte-27 (Atoh8 flox/flox ;Col2a1-Cre) and a germline-(Atoh8 flox/flox ;Prx1-Cre female ) specific Cre allele. In 28 both strains, Atoh8 deletion leads to a reduced skeletal size of the axial and appendicular 29 bones, but the stages of phenotypic manifestations differ. While we observed obviously 30 shortened bones in Atoh8 flox/flox ;Col2a1-Cre mice only postnatally, the bones of 31 Atoh8 flox/flox ;Prx1-Cre female mice are characterized by a reduced bone length already at 32 prenatal stages. Detailed histological and molecular investigations revealed reduced zones 33 of proliferating and hypertrophic chondrocytes. In addition, Atoh8 deletion identified Atoh8 as 34 a positive regulator of chondrocyte proliferation. As increased Atoh8 expression is found in 35 the region of prehypertrophic chondrocytes where the expression of Ihh, a main regulator of 36 chondrocyte proliferation and differentiation, is induced, we investigated a potential 37 interaction of Atoh8 function and Ihh signaling. By activating Ihh signaling with 38 Purmorphamine we demonstrate that Atoh8 regulates chondrocyte proliferation in parallel or 39 downstream of Ihh signaling while it acts on the onset of hypertrophy upstream of Ihh likely 40 by modulating Ihh expression levels.41 42 Introduction 43 During endochondral ossification, bones are formed by a multistep process, which includes 44 the formation of a cartilage template of the later skeletal element and its subsequent 45 replacement by bone. The cartilage anlagen originate in mesenchymal cells, which condense 46 and differentiate into chondrocytes. These chondrocytes proliferate and express the 47 extracellular matrix protein Collagen type 2 (Col2) [1]. Two subtypes of proliferating 48 chondrocytes can be distinguished: round, slow proliferating cells at the end of the cartilage 49 elements (round/resting chondrocytes) and flat, highly proliferating cells organized in 3 50 columns towards the hypertrophic region (columnar chondrocytes). When the cartilage 51 anlagen reach a critical size, proliferating chondrocytes in their center exit the cell cycle and 52 differentiate into Indian hedgehog (Ihh) producing, prehypertrophic [2, 3] and, subsequently, 53 Collagen type 10 (Col10) expressing, hypertrophic chondrocytes [4]. Eventually, blood 54 vessels invade the zone of hypertrophic chondrocytes and the hypertrophic cells are 55 replaced by bone and bone marrow. Postnatally, secondary ossification centers (SOC) are 56 formed at the ends of the endochondral long bones. Between the two regions of ossification, 57 parts of the embryonic cartilage, the so-called growth plates, remain to organize longitudinal 58 growth after birth [5]. As longitudinal bone growth depends on the balance between 59 chondrocyte proliferation and hyp...

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Section: Discussionmentioning

confidence: 99%

Atoh8 acts as a regulator of chondrocyte proliferation and differentiation in endochondral bones

Schroeder

Wuelling

Hoffmann

et al. 2019

Preprint

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“…To some extent, this result demonstrated that the signature could explain the nature of the Fuhrman grading system based upon nuclear size, and the shape and prominence of nucleoli . ATOH8 is recognized as a transcriptional factor that has important roles in cell differentiation and developmental biology . ATP1A3 and CNGA1 are important in cellular energy metabolism, while CHMP4C belongs to the chromatin‐modifying protein family and is associated with nucleus organization .…”

Section: Discussionmentioning

confidence: 99%

Identification and validation of an eight‐gene expression signature for predicting high Fuhrman grade renal cell carcinoma

Wan

Zhu

Han

et al. 2017

Intl Journal of Cancer

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Clear cell renal cell carcinoma (ccRCC) is a malignancy with heterogeneous outcomes. Currently, renal mass biopsies are commonly employed to extract disease characteristics and aid prognosis. Although the pathological diagnosis of malignant disease is accurate in contemporary reports, the classification of Fuhrman grade using biopsy specimens remains far from promising. To generate a gene signature to distinguish high-grade ccRCC, we used the cancer genome atlas (TCGA) database to develop a gene expression signature for distinguishing high-grade (G3/4) from low-grade (G1/2) disease. The expression profile was further validated for performance and clinical use in 283 frozen renal cancer samples and 127 ex vivo renal mass biopsy samples, respectively. The area under curve (AUC) was used to quantify discriminative ability and was compared using the De-long test. Using the discovery dataset, we identified a 24-gene signature for high-grade disease with an AUC of 0.884. After applied to the development dataset, an eight-gene profile was defined and achieved an AUC of 0.823. Accuracy of eight-gene panel was maintained in the renal mass biopsies (RMB) samples (AUC = 0.821). In summary, using three-stage design, we validated an eight-gene expression signature for predicting high Fuhrman grade of ccRCC. This tool may help to reveal the characteristics of ccRCC biopsy specimens.

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“…Of particular note, the bHLH transcription factor ATOH8 was recently shown to interact specifically with CnAβ but not CnAα [30]. ATOH is involved in skeletal muscle and cardiac development [31, 32], however its role in heart disease has not yet been explored.…”

Section: Calcineurin Structure and Regulationmentioning

confidence: 99%

Calcineurin signaling in the heart: The importance of time and place

Parra

Rothermel

2017

Journal of Molecular and Cellular Cardiology

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The calcium-activated protein phosphatase, calcineurin, lies at the intersection of protein phosphorylation and calcium signaling cascades, where it provides an essential nodal point for coordination between these two fundamental modes of intracellular communication. In excitatory cells, such as neurons and cardiomyocytes, that experience rapid and frequent changes in cytoplasmic calcium, calcineurin protein levels are exceptionally high, suggesting that these cells require high levels of calcineurin activity. Yet, it is widely recognized that excessive activation of calcineurin in the heart contributes to pathological hypertrophic remodeling and the progression to failure. How does a calcium activated enzyme function in the calcium-rich environment of the continuously contracting heart without pathological consequences? This review will discuss the wide range of calcineurin substrates relevant to cardiovascular health and the mechanisms calcineurin uses to find and act on appropriate substrates in the appropriate location while potentially avoiding others. Fundamental differences in calcineurin signaling in neonatal verses adult cardiomyocytes will be addressed as well as the importance of maintaining heterogeneity in calcineurin activity across the myocardium. Finally, we will discuss how circadian oscillations in calcineurin activity may facilitate integration with other essential but conflicting processes, allowing a healthy heart to reap the benefits of calcineurin signaling while avoiding the detrimental consequences of sustained calcineurin activity that can culminate in heart failure.

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The Transcription Factor Atonal homolog 8 Regulates Gata4 and Friend of Gata-2 during Vertebrate Development

Cited by 32 publications

References 65 publications

Atoh8 acts as a regulator of chondrocyte proliferation and differentiation in endochondral bones

Atoh8 acts as a regulator of chondrocyte proliferation and differentiation in endochondral bones

Identification and validation of an eight‐gene expression signature for predicting high Fuhrman grade renal cell carcinoma

Calcineurin signaling in the heart: The importance of time and place

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