PAX-3 EXPRESSION IN SEGMENTAL MESODERM MARKS EARLY STAGES IN MYOGENICCELL SPECIFICATION

Specification of the myogenic lineage begins prior to gastrulation and culminates in the emergence of determined myogenic precursor cells fr om the somites.The myoD family (MDF) of transcriptional activators con trols late step(s) in myogenic specification that are closely followed by terminal muscle differentiation. Genes expressed in myogenic: spec ification at stages earlier than MDFs are unknown. The Pax-3 gene is e xpressed in all the cells of the caudal segmental plate, the early mes oderm compartment that contains the precursors of skeletal muscle. As somites form from the segmental plate and mature, Pax-3 expression is progressively modulated. Beginning at the time of segmentation, Pax-3 becomes repressed in the ventral half of the somite, leaving Pax-3 exp ression only in the dermomyotome. Subsequently, differential modulatio n of Pax-3 expression levels delineates the medial and lateral halves of the dermomyotome, which contain precursors of axial (back) muscle a nd limb muscle, respectively. Pax-3 expression is then repressed as de rmomyotome-derived cells activate MDFs. Quail-chick chimera and ablati on experiments confirmed that the migratory precursors of limb muscle continue to express Pax-3 during migration. Since limb muscle precurso rs do not activate MDFs until 2 days after they leave the somite, Pax- 3 represents the first molecular marker for this migratory cell popula tion. A null mutation of the mouse Pax-3 gene, Splotch, produces major disruptions in early limb muscle development (Franz, T., Kothary, R., Surani, M. A. H.,Halata, Z. and Grim, M. (1993) Anat. Embryol. 187, 1 53-160; Goulding, M., Lumsden, A. and Paquette, A. (1994) Development 120, 957-971). We conclude, therefore, that Pax-3 gene expression in t he paraxial mesoderm marks earlier stagesin myogenic specification tha n MDFs and plays a crucial role in the specification and/or migration of limb myogenic precursors.