Positional cloning of heart and soul reveals multiple roles for PKC lambdain zebrafish organogenesis

Background: The Par-3/Par-6/aPKC complex is a key regulator of cell polarit y in a number of systems. In Drosophila, this complex acts at the zonula ad herens (adherens junctions) to establish epithelial polarity and helps to o rient the mitotic spindle during asymmetric neuroblast divisions. In MDCKII cells, this complex localizes to the zonula. occludens (tight junctions) a nd appears to regulate epithelial polarity. However, the in vivo role of th is complex during vertebrate embryogenesis is not known, due to the lack of relevant mutations. Results: We have positionally cloned the zebrafish heart and soul (has) mut ation, which affects the morphogenesis of several embryonic tissues, and sh ow that it encodes atypical protein kinase C lambda (aPKC lambda). We find that loss of aPKC lambda affects the formation and maintenance of the zonul a adherens in the polarized epithelia of the retina, neural tube, and diges tive tract, leading to novel phenotypes, such as the formation of multiple lumens in the developing intestine. In addition, has mutants display defect s in gut looping and endodermal organ morphogenesis that appear to be indep endent of the defects in epithelial polarity. Finally, we show that loss of aPKC lambda leads to defects in spindle orientation during progenitor cell divisions in the neural retina. Conclusions: Our results show that aPKC lambda is required for the formatio n and maintenance of the zonula. adherens during early epithelial developme nt in vertebrates and demonstrate a previously undescribed yet critical rol e for this protein in organ morphogenesis. Furthermore, our studies identif y the first genetic locus regulating the orientation of cell division in ve rtebrates.