title: Scapula development is governed by genetic interactions of Pbx1 with its family members and with Emx2 via their cooperative control of Alx1.
abstract: The genetic pathways underlying shoulder blade development are largely unknown, as gene networks controlling limb morphogenesis have limited influence on scapula formation. Analysis of mouse mutants for Pbx and Emx2 genes has suggested their potential roles in girdle development. In this study, by generating compound mutant mice, we examined the genetic control of scapula development by Pbx genes and their functional relationship with Emx2. Analyses of Pbx and Pbx1;Emx2 compound mutants revealed that Pbx genes share overlapping functions in shoulder development and that Pbx1 genetically interacts with Emx2 in this process. Here, we provide a biochemical basis for Pbx1;Emx2 genetic interaction by showing that Pbx1 and Emx2 can bind specific DNA sequences as heterodimers. Moreover, the expression of genes crucial for scapula development is altered in these mutants, indicating that Pbx genes act upstream of essential pathways for scapula formation. In particular, expression of Alx1, an effector of scapula blade patterning, is absent in all compound mutants. We demonstrate that Pbx1 and Emx2 bind in vivo to a conserved sequence upstream of Alx1 and cooperatively activate its transcription via this potential regulatory element. Our results establish an essential role for Pbx1 in genetic interactions with its family members and with Emx2 and delineate novel regulatory networks in shoulder girdle development.
authors.affiliation: Department of Cell and Developmental Biology, Weill Medical College of Cornell University, 1300 York Avenue, New York, NY 10021, USA.
authors.forename: Terence D
authors.initials: TD
authors.lastname: Capellini
authors.forename: Giulia
authors.initials: G
authors.lastname: Vaccari
authors.forename: Elisabetta
authors.initials: E
authors.lastname: Ferretti
authors.forename: Sebastian
authors.initials: S
authors.lastname: Fantini
authors.forename: Mu
authors.initials: M
authors.lastname: He
authors.forename: Massimo
authors.initials: M
authors.lastname: Pellegrini
authors.forename: Laura
authors.initials: L
authors.lastname: Quintana
authors.forename: Giuseppina
authors.initials: G
authors.lastname: Di Giacomo
authors.forename: James
authors.initials: J
authors.lastname: Sharpe
authors.forename: Licia
authors.initials: L
authors.lastname: Selleri
authors.forename: Vincenzo
authors.initials: V
authors.lastname: Zappavigna
mesh_terms: D000818:Animals; D001483:Base Sequence; D001665:Binding Sites; D003433:Crosses, Genetic; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D019281:Dimerization; D020869:Gene Expression Profiling; D018507:Gene Expression Regulation, Developmental; D018398:Homeodomain Proteins / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D008957:Models, Genetic; D008969:Molecular Sequence Data; D009154:Mutation; D000075062:Pre-B-Cell Leukemia Transcription Factor 1; D012540:Scapula / Q000196:embryology* / Q000502:physiology; D012689:Sequence Homology, Nucleic Acid; D012782:Shoulder / Q000196:embryology; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism*; D000099260:Empty Spiracles Homeobox Proteins
chemical_list: D004268:DNA-Binding Proteins; D018398:Homeodomain Proteins; D000075062:Pre-B-Cell Leukemia Transcription Factor 1; D014157:Transcription Factors; D000099260:Empty Spiracles Homeobox Proteins; C489986:Alx1 protein, mouse; C481797:Pbx1 protein, mouse