ATOH8, a regulator of skeletal myogenesis in the hypaxial myotome of the trunk

Balakrishnan-Renuka, Ajeesh; Morosan-Puopolo, Gabriela; Yusuf, Faisal; Abduelmula, Aisha; Chen, Jingchen; Zoidl, Georg; Philippi, Susanne; Dai, Fangping; Brand‐Saberi, Beate

doi:10.1007/s00418-013-1155-0

Cited by 23 publications

(21 citation statements)

References 37 publications

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“…Here we have investigated the role of Atoh8, a less well characterized member of the protein family, which is widely expressed in the developing embryo [8,9,14,38,39].…”

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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“…Here we have investigated the role of Atoh8, a less well characterized member of the protein family, which is widely expressed in the developing embryo [8,9,14,38,39].…”

Section: Discussionmentioning

confidence: 99%

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

Schroeder

Wuelling

Hoffmann

et al. 2019

Preprint

Self Cite

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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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“…Atoh8 is expressed in multiple tissues during embryonic development [ 1 – 5 ]. In the developing pancreas, it is initially found in the mesenchyme and later in differentiating epithelial (endocrine and exocrine) cells [ 3 ].…”

Section: Resultsmentioning

confidence: 99%

“…Atonal Homolog 8 (Atoh8) is a basic helix-loop-helix (bHLH) transcription factor highly conserved across species and expressed in multiple organs during embryonic development [ 1 – 5 ]. Atoh8 is thought to participate in differentiation programs even though its precise molecular functions remain largely unknown.…”

Section: Introductionmentioning

confidence: 99%

“…In mice, Atoh8 has been involved in kidney and liver development [ 2 , 9 ]. It has also been implicated in the development of retina and skeletal muscle in chicken and zebrafish [ 1 , 5 , 10 ]. In humans, ATOH8 has been shown to contribute to shear stress stimulated endothelial differentiation during embryonic endothelial development [ 11 ], to participate in muscle fiber regeneration [ 12 ] and to repress stem cell genes in hepatocellular carcinoma cells [ 13 ].…”

Section: Introductionmentioning

confidence: 99%

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Generation of a Conditional Allele of the Transcription Factor Atonal Homolog 8 (Atoh8)

et al. 2016

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Atonal Homolog 8 (Atoh8) is a basic helix-loop-helix (bHLH) transcription factor that is highly conserved across species and expressed in multiple tissues during embryogenesis. In the developing pancreas, Atoh8 is expressed in endocrine progenitors but declines in hormone-positive cells, suggesting a role during early stages of the endocrine differentiation program. We previously generated a whole-body Atoh8 knockout but early lethality of null embryos precluded assessment of Atoh8 functions during organ development. Here we report the generation of a conditional Atoh8 knockout mouse strain by insertion of two loxP sites flanking exon 1 of the Atoh8 gene. Pancreas-specific Atoh8 knockout (Atoh8 Δpanc) mice were obtained by mating this strain with a Pdx1-Cre transgenic line. Atoh8 Δpanc mice were born at the expected mendelian ratio and showed normal appearance and fertility. Pancreas weight and gross pancreatic morphology were normal. All pancreatic cell lineages were present, although endocrine δ (somatostatin) cells were modestly augmented in Atoh8 Δpanc as compared to control neonates. This increase did not affect whole-body glucose tolerance in adult knockout animals. Gene expression analysis in embryonic pancreases at the time of the major endocrine differentiation wave revealed modest alterations in several early endocrine differentiation markers. Together, these data argue that Atoh8 modulates activation of the endocrine program but it is not essential for pancreas formation or endocrine differentiation in the mouse. Given the ubiquitous expression pattern of Atoh8, the availability of a mouse strain carrying a conditional allele for this gene warrants further studies using temporally regulated Cre transgenic lines to elucidate time or cell-autonomous functions of Atoh8 during development and in the adult.

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ATOH8, a regulator of skeletal myogenesis in the hypaxial myotome of the trunk

Cited by 23 publications

References 37 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

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

Generation of a Conditional Allele of the Transcription Factor Atonal Homolog 8 (Atoh8)

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