Cardiac Progenitor Cells of the First and Second Heart Fields.

The heart forms from the first and second heart fields, which contribute to distinct regions of the myocardium. This is supported by clonal analyses, which identify corresponding first and second cardiac cell lineages in the heart. Progenitor cells of the second heart field and its sub-domains are controlled by a gene regulatory network and signaling pathways, which determine their behavior.

Messenger RNA in differentiating muscle cells-my experience in François Gros' lab in the 1970s and 80s.

I joined François Gros' laboratory as a postdoc at the end of 1971 and continued working with him as a research scientist until 1987, when I became an independent group leader at the Institut Pasteur. In the early 1970s, it was the beginning of research in his lab on muscle cell differentiation, as a model eukaryotic system for studying mRNAs and gene regulation. In this article, I recount our work on myogenesis and mention the other research themes in his lab and the people concerned.

M-Cadherin Is a PAX3 Target During Myotome Patterning.

PAX3 belongs to the paired-homeobox family of transcription factors and plays a key role as an upstream regulator of muscle progenitor cells during embryonic development. -mutant embryos display impaired somite development, yet the consequences for myotome formation have not been characterized. The early myotome is formed by PAX3-expressing myogenic cells that delaminate from the dermomyotomal lips and migrate between the dermomyotome and sclerotome where they terminally differentiate.

PAX3 Confers Functional Heterogeneity in Skeletal Muscle Stem Cell Responses to Environmental Stress.

Muscle satellite cells (MuSCs) are the quiescent muscle stem cells required for adult skeletal muscle repair. The impact of environmental stress such as pollution on MuSC behavior remains unexplored. We evaluated the impact of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) exposure, a ubiquitous and highly toxic pollutant, on MuSCs by combining in vivo mouse molecular genetic models with ex vivo studies.

The deployment of cell lineages that form the mammalian heart.

The function of the mammalian heart depends on the interplay between different cardiac cell types. The deployment of these cells, with precise spatiotemporal regulation, is also important during development to establish the heart structure. In this Review, we discuss the diverse origins of cardiac cell types and the lineage relationships between cells of a given type that contribute to different parts of the heart.

The role of Pitx2 and Pitx3 in muscle stem cells gives new insights into P38α MAP kinase and redox regulation of muscle regeneration.

Skeletal muscle regeneration depends on satellite cells. After injury these muscle stem cells exit quiescence, proliferate and differentiate to regenerate damaged fibres. We show that this progression is accompanied by metabolic changes leading to increased production of reactive oxygen species (ROS).

Gene regulatory networks and cell lineages that underlie the formation of skeletal muscle.

Skeletal muscle in vertebrates is formed by two major routes, as illustrated by the mouse embryo. Somites give rise to myogenic progenitors that form all of the muscles of the trunk and limbs. The behavior of these cells and their entry into the myogenic program is controlled by gene regulatory networks, where paired box gene 3 () plays a predominant role.

Tissue Differentiation: A Personal Account of Research on Myogenesis and Cardiogenesis.

In this essay I trace my own research experience as a developmental biologist, from the study of cell differentiation in vitro to tissue formation and regeneration in vivo. Beginning with a thesis on histone modifications, I went on to study gene regulation during myogenesis, first in muscle cells in culture and then in the mouse embryo. Later, we also worked on muscle regeneration in the adult.

Progressive developmental restriction, acquisition of left-right identity and cell growth behavior during lobe formation in mouse liver development.

To identify cell-based decisions implicated in morphogenesis of the mammalian liver, we performed clonal analysis of hepatocytes/hepatoblasts in mouse liver development, using a knock-in allele of Hnf4a/laacZ This transgene randomly undergoes a low frequency of recombination that generates a functional lacZ gene that produces β-galactosidase in tissues in which Hnf4a is expressed. Two types of β-galactosidase-positive clones were found. Most have undergone three to eight cell divisions and result from independent events (Luria-Delbrück fluctuation test); we calculate that they arose between E8.

Endothelial cell specification in the somite is compromised in Pax3-positive progenitors of Foxc1/2 conditional mutants, with loss of forelimb myogenesis.

Pax3 and Foxc2 have been shown genetically to mutually repress each other in the mouse somite. Perturbation of this balance in multipotent cells of the dermomyotome influences cell fate; upregulation of Foxc2 favours a vascular fate, whereas higher levels of Pax3 lead to myogenesis. Foxc1 has overlapping functions with Foxc2.

Fine-tuning the onset of myogenesis by homeobox proteins that interact with the Myf5 limb enhancer.

Skeletal myogenesis in vertebrates is initiated at different sites of skeletal muscle formation during development, by activation of specific control elements of the myogenic regulatory genes. In the mouse embryo, Myf5 is the first myogenic determination gene to be expressed and its spatiotemporal regulation requires multiple enhancer sequences, extending over 120 kb upstream of the Mrf4-Myf5 locus. An enhancer, located at -57/-58 kb from Myf5, is responsible for its activation in myogenic cells derived from the hypaxial domain of the somite, that will form limb muscles.

Pitx2 and Pitx3 transcription factors: two key regulators of the redox state in adult skeletal muscle stem cells and muscle regeneration.

Adult tissue homeostasis and regeneration rely on tissue stem cell populations that generate committed precursors and differentiated cells while maintaining a pool of stem cells. In adult skeletal muscle, such cells, called satellite cells, remain quiescent at the periphery of muscle fibers. Upon injury they undergo activation, proliferation and differentiation to replace damaged fibers and also self-renew to reconstitute the muscle stem cell pool.

PAX3 and PAX7 as upstream regulators of myogenesis.

Like other subclasses within the PAX transcription factor family, PAX3 and PAX7 play important roles in the emergence of a number of different tissues during development. PAX3 regulates neural crest and, together with its orthologue PAX7, is also expressed in parts of the central nervous system. In this chapter we will focus on their role in skeletal muscle.

Heart fields and cardiac morphogenesis.

In this review, we focus on two important steps in the formation of the embryonic heart: (i) the progressive addition of late differentiating progenitor cells from the second heart field that drives heart tube extension during looping morphogenesis, and (ii) the emergence of patterned proliferation within the embryonic myocardium that generates distinct cardiac chambers. During the transition between these steps, the major site of proliferation switches from progenitor cells outside the early heart to proliferation within the embryonic myocardium. The second heart field and ballooning morphogenesis concepts have major repercussions on our understanding of human heart development and disease.

Cardiac cell lineages that form the heart.

Myocardial cells ensure the contractility of the heart, which also depends on other mesodermal cell types for its function. Embryological experiments had identified the sources of cardiac precursor cells. With the advent of genetic engineering, novel tools have been used to reconstruct the lineage tree of cardiac cells that contribute to different parts of the heart, map the development of cardiac regions, and characterize their genetic signature.

Interactions with John Gurdon--muscle as a mesodermal read-out and the community effect.

John Gurdon has made major contributions to developmental biology in addition to his Nobel prize winning work on nuclear reprogramming. With the frog, Xenopus, as a vertebrate model, his work on mesoderm induction led him to identify a community effect required for tissue differentiation after progenitor cells have entered a specific mesodermal programme. It is in the context of this biologically important concept, with myogenesis as an example, that we have had most scientific exchanges.

Notch regulation of myogenic versus endothelial fates of cells that migrate from the somite to the limb.

Multipotent Pax3-positive (Pax3(+)) cells in the somites give rise to skeletal muscle and to cells of the vasculature. We had previously proposed that this cell-fate choice depends on the equilibrium between Pax3 and Foxc2 expression. In this study, we report that the Notch pathway promotes vascular versus skeletal muscle cell fates.

Redox regulation by Pitx2 and Pitx3 is critical for fetal myogenesis.

During development, major metabolic changes occur as cells become more specialized within a lineage. In the case of skeletal muscle, differentiation is accompanied by a switch from a glycolytic proliferative progenitor state to an oxidative postmitotic differentiated state. Such changes require extensive mitochondrial biogenesis leading to increased reactive oxygen species (ROS) production that needs to be balanced by an antioxidant system.

Prdm1 functions in the mesoderm of the second heart field, where it interacts genetically with Tbx1, during outflow tract morphogenesis in the mouse embryo.

Congenital heart defects affect at least 0.8% of newborn children and are a major cause of lethality prior to birth. Malformations of the arterial pole are particularly frequent.

Gene regulatory networks and transcriptional mechanisms that control myogenesis.

We discuss the upstream regulators of myogenesis that lead to the activation of myogenic determination genes and subsequent differentiation, focusing on the mouse model. Key upstream genes, such as Pax3 and Pax7, Six1 and Six4, or Pitx2, participate in gene regulatory networks at different sites of skeletal muscle formation. MicroRNAs also intervene, with emerging evidence for the role of other noncoding RNAs.