Pbx1/Pbx2 govern axial skeletal development by controlling Polycomb and Hox in mesoderm and Pax1/Pax9 in sclerotome.
The post-cranial axial skeleton consists of a metameric series of vertebral bodies and intervertebral discs, as well as adjoining ribs and sternum. Patterning of individual vertebrae and distinct regions of the vertebral column is accomplished by Polycomb and Hox proteins in the paraxial mesoderm, while their subsequent morphogenesis depends partially on Pax1/Pax9 in the sclerotome. In this study, we uncover that Pbx1/Pbx2 are co-expressed during successive stages of vertebral and rib development. Next, by exploiting a Pbx1/Pbx2 loss-of-function mouse, we show that decreasing Pbx2 dosage in the absence of Pbx1 affects axial development more severely than single loss of Pbx1. Pbx1/Pbx2 mutants exhibit a homogeneous vertebral column, with loss of vertebral identity, rudimentary ribs, and rostral hindlimb shifts. Of note, these axial defects do not arise from perturbed notochord function, as cellular proliferation, apoptosis, and expression of regulators of notochord signaling are normal in Pbx1/Pbx2 mutants. While the observed defects are consistent with loss of Pbx activity as a Hox-cofactor in the mesoderm, we additionally establish that axial skeletal patterning and hindlimb positioning are governed by Pbx1/Pbx2 through their genetic control of Polycomb and Hox expression and spatial distribution in the mesoderm, as well as of Pax1/Pax9 in the sclerotome.
Capellini
Terence D
TD
Department of Cell and Developmental Biology, Weill Medical College of Cornell University, 1300 York Avenue, New York, NY 10021, USA.
Zewdu
Rediet
R
Di Giacomo
Giuseppina
G
Asciutti
Stefania
S
Kugler
Jamie E
JE
Di Gregorio
Anna
A
Selleri
Licia
L
D000818:Animals; D019521:Body Patterning / Q000502:physiology*; D001973:Bromodeoxyuridine; D018628:Gene Dosage; D018507:Gene Expression Regulation, Developmental / Q000235:genetics / Q000502:physiology*; D018398:Homeodomain Proteins / Q000235:genetics / Q000378:metabolism*; D007150:Immunohistochemistry; D017403:In Situ Hybridization; D051379:Mice; D009154:Mutation / Q000235:genetics; D051764:PAX9 Transcription Factor; D051761:Paired Box Transcription Factors / Q000378:metabolism; D063146:Polycomb-Group Proteins; D000075062:Pre-B-Cell Leukemia Transcription Factor 1; D011518:Proto-Oncogene Proteins / Q000235:genetics / Q000378:metabolism*; D012097:Repressor Proteins / Q000378:metabolism; D013131:Spine / Q000196:embryology*; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism*
D018398:Homeodomain Proteins; D051764:PAX9 Transcription Factor; D051761:Paired Box Transcription Factors; C488759:Pax9 protein, mouse; C481797:Pbx1 protein, mouse; C490382:Pbx2 protein, mouse; D063146:Polycomb-Group Proteins; D000075062:Pre-B-Cell Leukemia Transcription Factor 1; D011518:Proto-Oncogene Proteins; D012097:Repressor Proteins; D014157:Transcription Factors; C070835:PAX1 transcription factor; D001973:Bromodeoxyuridine