Life Science Open Day | 2006 | Weizmann Institute of Science

972 8 934 3715

Department of Biological Regulation

972 8 934 4116

eldad.tzahor@weizmann.ac.il

For the past few years, our lab has been focusing on the identification of candidate signaling molecules and tissue-specific transcription factors that regulate cardiac and skeletal muscle formation during early vertebrate embryogenesis.1,2 Based on previous and ongoing studies in our lab (see below), we propose that the cardiac and craniofacial developmental programs are tightly linked. Accordingly, insults to any component of this cardiocraniofacial morphogenetic field may lead to both cardiac and craniofacial abnormalities.

The developing heart is a specialized muscular vessel that serves as a pump for both the systemic and pulmonary circuits (Panel A). This extremely complicated organ is highly sensitive to genetic perturbations, which are reflected in the numerous congenital heart defects that affect ~1% of all live births. The multiplicity of cardiac progenitor populations in various vertebrate species is an emerging area of intense focus in many laboratories, due to the enormous therapeutic potential of these avenues for treating heart disease.

During early embryogenesis, heart and skeletal muscle progenitor cells are thought to derive from distinct regions of the mesoderm (i.e., lateral plate mesoderm and paraxial mesoderm, respectively). In the present study,3 we have employed both in vitro and in vivo experimental systems in the avian embryo to explore how mesoderm progenitors in the head differentiate into both heart and skeletal muscles. Utilizing fate mapping studies, gene expression analyses, and manipulations of signaling pathways in the chick embryo, we demonstrate that cells from the cranial paraxial mesoderm contribute to both myocardial and endocardial cell populations within the cardiac outflow tract. We further show that bone morphogenic protein (BMP4) signaling affects the specification of mesoderm cells in the head: application of BMP4 to chick embryos, both in vitro and in vivo, induces cardiac differentiation in the cranial paraxial mesoderm, and blocks the differentiation of skeletal muscle precursors in these cells. Our results demonstrate that cells within the cranial paraxial mesoderm play a vital role in cardiogenesis, as a new source of cardiac progenitors that populate the cardiac outflow tract in vivo (Panel B).3

Craniofacial development requires the orchestrated integration of multiple interactions among progenitor cells derived from both the cranial paraxial mesoderm and the cranial neural crest (CNC, Panel C). In the vertebrate head, mesoderm-derived cells fuse together to form a myofiber, which is attached to specific CNC-derived skeletal elements in a highly coordinated manner. Although it has long been suggested that the CNC plays an indirect role in the formation of the head musculature, the precise molecular underpinnings of this exquisitely tuned process, and the significance of the CNC’s contribution to it, are far less clear. In a recent study,4 we analyzed head skeletal muscle patterning and differentiation in vivo, in three mouse models involving genetic perturbations of CNC development, as well as in CNC-ablated chick embryos. Our results demonstrate that although early specification of the skeletal muscle lineage is CNC-independent, CNC cells play an important role at later developmental stages, regulating the expression patterns of myogenic genes, the migration and axial registration of the mesoderm cells, and the subsequent differentiation of myoblasts in the branchial arches. This study supports a model in which CNC cells control craniofacial development and patterning by regulating positional interactions with mesoderm-derived muscle progenitors that together shape the cranial musculoskeletal architecture during vertebrate embryogenesis. A deeper understanding of mesodermal lineage specification in the vertebrate head is expected to provide insights into normal as well as pathological aspects of heart and craniofacial development.

Cardiac and skeletal muscle lineage specification during vertebrate embryogenesis

Eldad Tzahor

Libbat Tirosh

Ariel Rinon

Elisha Nathan

Shlomi Lazar

Hadas Elhanany

Adi Neufeld

Carmel Bar

Elik Chapnik

www.weizmann.ac.il/Biological_Regulation/NewFiles/tzahor.html

Selected publications:1. Tzahor E, Lassar AB. (2001) Wnt signals from the neural tube

block ectopic cardiogenesis. Genes & Dev. 15(3): 255-260.2. Tzahor E, Kempf H, Mootoosamy RC, Poon AC, Abzhanov A,

Tabin CJ, Dietrich S, Lassar AB. (2003) Antagonists of Wnt and BMP signaling induce the formation of vertebrate head muscle. Genes & Dev. 17(24): 3087-3099.

3. Tirosh-Finkel L, Elhanany H, Rinon A, Tzahor E, (2006) Mesoderm progenitor cells of common origin contribute to the head musculature and the cardiac outflow tract. Development, in press.

4. Rinon A, Shlomi L, Neufeld A, Marshall H, Buechmann S, Taketo M, Sommer L, Krumlauf R, Tzahor E, (2006) Cranial neural crest cells affect head muscle patterning and differentiation during vertebrate embryogenesis. Submitted for publication.

AcknowledgementsOur work is supported by research grants from the Estelle Funk

Foundation for Biomedical Research, Ruth & Allen Ziegler, MINERVA, and a GIF Young Investigator Award (E.T.). Eldad Tzahor is the incumbent of the Gertrude and Philip Nollman Career Development Chair.

Fig. 1 Cranial paraxial mesoderm cells as a model to study cardiogenesis and myogenesis during vertebrate embryogenesis A. The development of the chambered heart is initiated during early embryogenesis by the recruitment of multiple cardiac progenitor populations from the lateral mesoderm. B. Cranial paraxial mesoderm cells migrate through the branchial arches (also known as pharyngeal arches), where they differentiate into the skeletal muscle lineage. Our new study demonstrates that some of these mesodermal cells can migrate further towards the aortic sac, which connects the branchial arches to the outflow tract. These cells eventually contribute to the myocardium and endocardium of the outflow tract. The gradual shift from a skeletal muscle to a cardiac cell fate is correlated with the spatiotemporal expression of BMP4. Moreover, ectopic application of BMP4 both in vitro and in vivo promotes cardiogenesis in the cranial paraxial mesoderm, and blocks the skeletal muscle differentiation program. C. The vertebrate head is an excellent developmental system for the study of both patterning and differentiation programs. During craniofacial development, progenitor cells derived from the cranial paraxial mesoderm fuse together to form a myofiber, which is attached to a specific skeletal element derived from the cranial neural crest in a highly coordinated manner. Loss- and gain-of-function experiments in both mouse and avian models demonstrate that skeletal muscle patterning and differentiation in the head are precisely regulated by the crosstalk between the mesoderm and neural crest cells.