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Group Dr. Christoph Schaub

Lineage commitment and lineage plasticity in the Drosophila musculature

How do cells become different from one another during development? Which mechanisms are mediating the maintenance of these differences? And which factors have the power to revoke the differentiated state? These questions represent fundamental challenges of developmental biology, which have been under investigation for decades.

My lab is interested in the molecular processes that drive the establishment and maintenance of the larval and adult skeletal musculature in Drosophila, representing an elegant and powerful in vivo model system to address these questions. With the recent advent of advanced methods, such as cell type specific, genome wide characterisation of gene expression (RNA-Seq), genome wide identification of transcription factor binding sites (ChIP-Seq), or genome wide characterisation of the chromatin regulatory landscape (e.g. by Assay for Transposase-Accessible Chromatin-Seq, ATAC-Seq) and therefore the possibility to analyse cell lineage commitment and plasticity mechanisms during embryonic and adult muscle development within a systems biology context, these challenges can be pushed to new frontiers.

Transcriptional regulation of muscle progenitor lineage commitment and muscle cell identity

 The Drosophila larval skeletal musculature is arranged in a highly stereotyped pattern of 30 muscle fibers per segment, each of which arises from an individual cell, the muscle founder cell. This cell has been primed to an individual fate by the expression of a characteristic combination of transcription factors, the muscle identity factors, and possesses the complete information for building the muscle that will arise from it. To form a particular muscle the muscle founder cell fuses with surrounding fusion competent myoblasts (FCMs) and endows these with its own genetic program, resulting in the differentiation of a syncytial, morphological distinct muscle fiber.

My group is interested in the mechanisms that govern lineage commitment and plasticity during embryonic skeletal muscle development in Drosophila on a genome wide level by combining classical genetic approaches and in vivo systems biology approaches.

Previous work established that the org-1 gene, encoding the Drosophila ortholog of the transcription factor Tbx1, which plays important roles during the development of the craniofacial and heart musculature in vertebrates, also plays an important role during skeletal and visceral myogenesis in Drosophila. In the developing larval skeletal musculature org-1 is expressed in a subset of muscle founder cells and acts as a newly identified muscle identity gene, which is crucial for the proper generation of the muscles arising from these cells. Adding an additional layer of regulation, Org-1 activates the expression of known muscle identity genes in the respective founder cells by direct binding to founder cell specific cis-regulatory modules (CRMs) as shown by ChIP (Chromatin immunoprecipitation) analysis.

 

 

To extract the information that is programmed by Org-1 and other muscle identity factors into the individual muscle founders we are characterising in a genome wide approach muscle founder cell specific transcriptomes as well as analyse the regulatory chromatin landscapes imposing lineage fate for individual muscle founder cells. For this purpose we are utilising the INTACT (Isolation of Nuclei Tagged in specific Cell Type) technique to separate the nuclei of different subtypes of muscle founder lineages from the total nuclear fraction derived from living embryos. These nuclei are used for the compilation of founder cell subtype specific RNA-Seq, ChIP-Seq and ATAC-Seq data sets.

 

 

 

Molecular mechanisms driving muscle dedifferentiation during muscle lineage reprogramming

 In addition to programming of cell fates, lineage reprogramming and transdifferentiation has become an increased focus of recent research since it was demonstrated that a variety of differentiated somatic cells can be used in vitro to derive induced Pluripotent Stem Cells (iPSCs) by ectopic expression of key transcription factors. This technology has been enhanced by the establishment of in vitro technologies that allow direct reprogramming of one somatic cell into another without an iPSC intermediate by expression of lineage restricted transcription factors.

Recently, our work has uncovered a naturally occurring in vivo direct lineage reprogramming process during the metamorphosis of the Drosophila musculature. It crucially depends on the T-Box transcription factor optomotor-blind-related-gene-1 (org-1), the Drosophila homolog of vertebrate TBX1, and includes dedifferentiation of somatic syncytial muscles into mononucleate myoblasts followed by redifferentiation into another type of syncytial muscles. This unusual process is reminiscent of the events that were described for muscle regeneration in newt.

 

 

In order to extend our understanding of the mechanisms that guide alary muscle dedifferentiation, and in vivo muscle dedifferentiation processes in general, my group address different aspects and regulatory instances of the dedifferentiation process.

The results from studying these factors and mechanisms as well as their regulatory interconnections during muscle dedifferentiation could also be relevant for the understanding of other dedifferentiation processes. A deeper understanding of the regulatory circuits that are utilized to reverse the differentiation state of a cell in vivo and change its fate could also enhance our ability to access technologies in regenerative medicine that take advantage of direct lineage reprogramming mechanisms.

 

 

 

Relevant publications

 

Reim I., Frasch M., Schaub C. (2017)

T-box genes in Drosophila mesoderm development. Current Topics in Developmental Biology 122, 161-193.

 

Schaub C., März J., Reim I., Frasch M. (2015)

Org-1-dependent lineage reprogramming generates the ventral longitudinal musculature of the Drosophila heart. Current Biology 25(4), 488-494.

 

Boukhatmi H. *, Schaub C. *, Bataillle L. *, Reim I., Frendo JL, Frasch M., Vincent A. (2014)

An Org-1/Tbx1-Tup/Islet1 transcriptional cascade reveals the existence of different types of alary muscles connecting internal organs in Drosophila. Development 141, 3761-3771 *shared first authorship.

 

Schaub C., Nagaso H., Jin H., Frasch, M. (2012)

Org-1, the Drosophila ortholog of Tbx1, is a direct activator of known identity genes during muscle specification. Development 139, 1001-1012.

 

Members

MSc Marcel Rose (PhD student)

BSc Tobias Böhm (Master student)