Early specification of limb muscle precursor cells by the homeobox gene Lbx1h.
During vertebrate embryogenesis, myogenic precursor cells of limb muscles delaminate from the ventro-lateral edge of the somitic dermomyotome and migrate to the limb buds, where they congregate into dorsal and ventral muscle masses. It has been proposed that the surrounding connective tissue controls muscle pattern formation in limbs. Regulatory molecules such as receptor tyrosine kinases like c-Met ( ref. 6) and those encoded by homeobox-containing genes, including c-Met (ref. 6), Tbx1 (ref. 7), Mox2 (ref. 8), Six1 and Six2 (ref. 9), Pitx2, Pax3 (refs 10,11) and Lbx1h (refs 12,13), are expressed in migrating limb precursor cells. The role of these genes in the patterning of limb muscles is unknown, although mutation of Pax3 or Met causes disruption of limb muscle development at an initial step, disturbing the epithelial-to-mesenchymal transition of the somitic epithelium. No limb muscle cells form in these mutants, and the early loss of myogenic precursor cells prevented an analysis of later functions of these genes during limb muscle development. Based on quail-chick chimaera studies, it was assumed that a cell-autonomous contribution of myogenic cells to the formation of individual limb muscles is negligible, and that an instructive role of limb mesenchyme is critical in this process. Here we show that Lbx1h determines migratory routes of muscle precursor cells in a cell-autonomous manner, thereby leading to the formation of distinct limb muscle patterns. Inactivation of Lbx1h, which is specifically expressed in migrating muscle precursor cells, led to a lack of extensor muscles in forelimbs and an absence of muscles in hindlimbs. The defect was caused by the failure of all muscle precursor cells of hindlimbs and of precursor cells of extensor muscles of forelimbs to migrate to their corresponding muscle anlagen. Our results demonstrate that Lbx1h is a key regulator of muscle precursor cell migration and is required for the acquisition of dorsal identities of forelimb muscles.
Schäfer
K
K
Institute of Physiological Chemistry, Martin-Luther-University Halle, 06097 Halle, Hollystr. 1, Germany.
Braun
T
T
D000818:Animals; D000831:Animals, Newborn; D030161:Avian Proteins; D004268:DNA-Binding Proteins / Q000235:genetics; D004622:Embryo, Mammalian / Q000378:metabolism; D005314:Embryonic and Fetal Development; D005121:Extremities / Q000196:embryology*; D018507:Gene Expression Regulation, Developmental; D005801:Genes, Homeobox / Q000235:genetics*; D017403:In Situ Hybridization; D051379:Mice; D009124:Muscle Proteins / Q000235:genetics*; D009132:Muscles / Q000166:cytology / Q000196:embryology / Q000378:metabolism*; D017570:MyoD Protein / Q000235:genetics; D051787:Myogenic Regulatory Factor 5; D000072041:PAX3 Transcription Factor; D051761:Paired Box Transcription Factors; D019859:Proto-Oncogene Proteins c-met / Q000235:genetics; D012333:RNA, Messenger / Q000235:genetics; D020825:T-Box Domain Proteins; D015534:Trans-Activators; D014157:Transcription Factors / Q000235:genetics
D030161:Avian Proteins; D004268:DNA-Binding Proteins; C113279:LBX1 protein, Gallus gallus; C491868:Lbx1h protein, mouse; D009124:Muscle Proteins; C497418:Myf5 protein, mouse; D017570:MyoD Protein; C057363:MyoD1 myogenic differentiation protein; D051787:Myogenic Regulatory Factor 5; D000072041:PAX3 Transcription Factor; C489409:PAX3 protein, human; D051761:Paired Box Transcription Factors; D012333:RNA, Messenger; D020825:T-Box Domain Proteins; C491573:Tbx1 protein, mouse; D015534:Trans-Activators; D014157:Transcription Factors; C068686:Pax3 protein, mouse; D019859:Proto-Oncogene Proteins c-met