Induction of Ectopic Olfactory Structures and Bone Morphogenetic Protein Inhibition by Rossy, a Group XII Secreted Phospholipase A₂

Abstract

The secreted phospholipases A₂ (sPLA₂s) comprise a family of small secreted proteins with the ability to catalyze the generation of bioactive lipids through glycophospholipid hydrolysis. Recently, a large number of receptor proteins and extracellular binding partners for the sPLA₂s have been identified, suggesting that these secreted factors might exert a subset of their broad spectrum of biological activities independently of their enzymatic activity. Here, we describe an activity for the sPLA₂ group XII (sPLA₂-gXII) gene during Xenopus laevis early development. In the ectoderm, sPLA₂-gXII acts as a neural inducer by blocking bone morphogenetic protein (BMP) signaling. Gain of function in embryos leads to ectopic neurogenesis and to the specification of ectopic olfactory sensory structures, including olfactory bulb and sensory epithelia. This activity is conserved in the Drosophila melanogaster, Xenopus, and mammalian orthologs and appears to be independent of the lipid hydrolytic activity. Because of its effect on olfactory neurogenesis, we have renamed this gene Rossy, in homage to the Spanish actress Rossy de Palma. We present evidence that Rossy/sPLA₂-gXII can inhibit the transcriptional activation of BMP direct-target gene reporters in Xenopus and mouse P19 embryonic carcinoma cells through the loss of DNA-binding activity of activated Smad1/4 complexes. Collectively, these data represent the first evidence for signaling cross talk between a secreted phospholipase A₂ and the BMP/transforming growth factor β pathways and identify Rossy/sPLA₂-gXII as the only factor thus far described which is sufficient to induce anterior sensory neural structures during vertebrate development.

ACKNOWLEDGMENTS

We thank Dan Stetler and Alison North for help with the confocal images, N. Marsh-Armstrong for the transgenic embryos, A. Hata for the Tlx2 reporter, and Dan Besser, Alin Vonica, and Joan Seoane for comments on the manuscript.

This work is funded by NIH grant HD32105 to A.H.B. and a Helen Hay Whitney Foundation fellowship to I.M.-S.