Abstract
The basic helix-loop-helix (bHLH) transcription factor Math6 (Atonal homolog 8; Atoh8) plays a crucial role in a number of cellular processes during embryonic development, iron metabolism and tumorigenesis. We report here on its involvement in cellular reprogramming from fibroblasts to induced pluripotent stem cells, in the maintenance of pluripotency and in early fate decisions during murine development. Loss of Math6 disrupts mesenchymal-to-epithelial transition during reprogramming and primes pluripotent stem cells towards the mesendodermal fate. Math6 can thus be considered a regulator of reprogramming and pluripotent stem cell fate. Additionally, our results demonstrate the involvement of Math6 in SMAD-dependent TGF beta signalling. We furthermore monitor the presence of the Math6 protein during these developmental processes using a newly generated Math6Flag-tag mouse. Taken together, our results suggest that Math6 counteracts TGF beta signalling and, by this, affects the initiating step of cellular reprogramming, as well as the maintenance of pluripotency and early differentiation.
Highlights
Atonal homolog 8 (Atoh8), that is, Mouse atonal homolog 6 (Math6), belongs to the group of basic helix loop helix transcription factors, which regulate the expression of genes required for cell commitment and differentiation
Math6 and the genes that are involved in reprogramming
To investigate the connection of TGF-β signalling in reprogramming, we investigate the connection of Math6 with Mesenchymal-to-Epithelial Transition (MET) and TGF-β signalling in reprogramming, we treated treated the reprogramming fibroblasts with a selective inhibitor of signalling
Summary
Atonal homolog 8 (Atoh8), that is, Mouse atonal homolog 6 (Math6), belongs to the group of basic helix loop helix (bHLH) transcription factors, which regulate the expression of genes required for cell commitment and differentiation. The bHLH transcription factors in general function either as transcriptional activators or repressors [1,2] and play important regulatory roles during developmental processes, such as myogenesis, neurogenesis and haematopoiesis, as well as the development of the gastrointestinal and reproductive tract [3]. Atoh possesses two highly conserved and functionally distinct basic DNA-binding domains, which are followed by two alpha–helices separated by a variable loop region (HLH). The HLH region thereby facilitates the formation of homo- and heterodimers [4]. Math was first described in the context of neurogenesis where it was found to be expressed in neuronal precursor cells of the ventricular zone and subsequently in differentiating neurons [5]. Like other bHLH transcription factors, Math was identified in the commitment and differentiation of
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