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Jelly belly protein activates the receptor tyrosine kinase Alk to specify visceral muscle pioneers

Abstract

The secreted protein Jelly belly (Jeb) is required for an essential signalling event in Drosophila muscle development. In the absence of functional Jeb, visceral muscle precursors are normally specified but fail to migrate and differentiate1. The structure and distribution of Jeb protein implies that Jeb functions as a signal to organize the development of visceral muscles1. Here we show that the Jeb receptor is the Drosophila homologue of anaplastic lymphoma kinase (Alk), a receptor tyrosine kinase of the insulin receptor superfamily. Human ALK was originally identified as a proto-oncogene, but its normal function in mammals is not known2. In Drosophila, localized Jeb activates Alk and the downstream Ras/mitogen-activated protein kinase cascade to specify a select group of visceral muscle precursors as muscle-patterning pioneers. Jeb/Alk signalling induces the myoblast fusion gene dumbfounded (duf; also known as kirre) as well as org-1, a Drosophila homologue of mammalian TBX1, in these cells.

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Figure 1: jeb specifies founder cell fates in the visceral mesoderm.
Figure 2: jeb-dependent Ras/MAPK signalling triggers founder cell specification in the visceral mesoderm.
Figure 3: Jeb acts through the receptor tyrosine kinase Alk to specify visceral muscle founder cells.
Figure 4: Jeb specifically binds with high affinity to Drosophila Alk and activates MAPK in mammalian tissue culture cells.

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Acknowledgements

We thank R. Krauss, M. Mlodzik, H. Nguyen and R. Nusse for comments. We acknowledge the Developmental Studies Hybridoma Bank and the Bloomington Stock Collection for providing antibodies and fly stocks. The Mount Sinai Confocal Microscopy Shared Resource Facility was supported, in part, with funding from a NIH-NCI shared resources grant. This research was supported by grants from the National Institutes of Health to M.F. (from NICHD and NIDDK) and to J.B.W. (from NHLBI and HHMI).

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Correspondence to Joseph B. Weiss or Manfred Frasch.

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Supplementary information

41586_2003_BFnature01916_MOESM1_ESM.pdf

Supplementary Figure 1: jeb prevents sns expression in visceral muscle founders, which are essential for visceral muscle formation. (PDF 780 kb)

41586_2003_BFnature01916_MOESM2_ESM.pdf

Supplementary Figure 2: Alk activity is required for visceral muscle founder specification and rescues midgut phenotypes in jeb mutant embryos. (PDF 832 kb)

41586_2003_BFnature01916_MOESM3_ESM.pdf

Supplementary Figure 3: Alk appears necessary for the association of Jeb with longitudinal axon tracts in the cns. (PDF 574 kb)

Supplementary Methods: Plasmid constructions, Antibodies and in situ hybridization probes (PDF 12 kb)

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Lee, HH., Norris, A., Weiss, J. et al. Jelly belly protein activates the receptor tyrosine kinase Alk to specify visceral muscle pioneers. Nature 425, 507–512 (2003). https://doi.org/10.1038/nature01916

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