Pbx1/Pbx2requirement for distal limb patterning is mediated by the hierarchical control of Hox gene spatial distribution andShhexpression
Author:
Capellini Terence D.12, Di Giacomo Giuseppina1, Salsi Valentina3, Brendolan Andrea1, Ferretti Elisabetta1, Srivastava Deepak4, Zappavigna Vincenzo13, Selleri Licia1
Affiliation:
1. Department of Cell and Developmental Biology, Cornell University Weill Medical School, New York, NY 10021, USA. 2. New York Consortium in Evolutionary Primatology, The Graduate School and University Center, The City University of New York, NY 10016, USA. 3. Department of Animal Biology, University of Modena-Reggio Emilia, Modena 41100, Italy. 4. Gladstone Institute of Cardiovascular Disease, Department of Pediatrics,University of California, San Francisco, CA 94158, USA.
Abstract
Vertebrate limb development occurs along three cardinal axes–proximodistal, anteroposterior and dorsoventral–that are established via the organization of signaling centers, such as the zone of polarizing activity (ZPA). Distal limb development, in turn, requires a molecular feedback loop between the ZPA expression of sonic hedgehog(Shh) and the apical ectodermal ridge. The TALE homeoprotein Pbx1 has been shown to be essential for proximal limb development. In this study, we first uncover that Pbx1 and Pbx2 are co-expressed in the lateral plate and early limb field mesoderm. Later, Pbx2 is expressed throughout the limb, unlike Pbx1, which is expressed only in the proximal bud. By exploiting a Pbx1/Pbx2 loss-of-function mouse model,we demonstrate that, despite the lack of limb abnormalities in Pbx2-deficient (Pbx2–/–) embryos,compound Pbx1–/–; Pbx2+/–mutants, in addition to their exacerbated proximal limb defects, exhibit novel and severe distal abnormalities. Additionally, we reveal that Pbx1–/–; Pbx2–/–embryos lack limbs altogether. Furthermore, we establish that, unlike in flies, where the leg develops independently of Hox and where the Pbx ortholog Exd is required for specification of proximal (but not distal) limbs,in vertebrates, distal limb patterning is Pbx1/Pbx2dependent. Indeed, we demonstrate that Pbx genetic requirement is mediated, at least in part, through their hierarchical control of Hox spatial distribution and Shh expression. Overall, we establish that, by controlling the spatial expression of Hox genes in the posterior limb and regulating ZPA function, Pbx1/Pbx2 exert a primary hierarchical function on Hox genes, rather than behaving merely as Hox ancillary factors.
Publisher
The Company of Biologists
Subject
Developmental Biology,Molecular Biology
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