Pbx1/Pbx2 govern axial skeletal development by controlling Polycomb and Hox in mesoderm and Pax1/Pax9 in sclerotome

Abstract

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.

Genomic characterization of Wilms' tumor suppressor 1 targets in nephron progenitor cells during kidney development

“…Leukocyte cell migration (Liu et al, 2005) 12.78 <0.001 Pbx1/Pbx2 coordinately regulate limb patterning and axial skeletal development (Capellini et al, 2006;Capellini et al, 2008) …”

Regulatory role for a conserved motif adjacent to the homeodomain of Hox10 proteins

“…However, even if such interaction occurs, it is not very probable that Pbx proteins mediate interactions between M1 and N-terminal region in the rib-repressing process. Genetic data supports this conclusion as inactivating mutations in Pbx genes are associated with deficient rib development (Capellini et al, 2008), which is the opposite to what would be expected for a Hox10 co-factor. Our analysis of Hoxa10 ST>AA also argues against an involvement of Pbx proteins in Hoxa10 rib-repressing activity.…”

“…Exd is able to bind both a hexapeptide located N-terminal to the homeodomain in many Hox proteins (Chan and Mann, 1996) and the UbdA motif, C-terminal to the homeodomain of Ubx and AbdA (Merabet et al, 2007). Exd (alone or together with Hth) has been shown to refine the DNAbinding properties of Hox proteins (Joshi et al, 2007;Slattery et al, 2011) vertebrate Hox proteins (Phelan et al, 1995), it is not clear from genetic experiments to what extent they contribute to Hox gene function in general or specificity in particular (Capellini et al, 2006;Capellini et al, 2008;Moens and Selleri, 2006).…”

Retinoid Signaling is a Context-Dependent Regulator of Embryonic Stem Cells

“…As Pbx proteins have been shown to dimerize with Hox proteins and act as a cofactor, we included here (Moens and Selleri 2006). Pbx2 is believed to be involved in the control of proximodistal axis formation in mouse (Capellini, Zewdu et al 2008). …”