Scube3 Is Expressed in Multiple Tissues during Development but Is Dispensable for Embryonic Survival in the Mouse

Abstract

The vertebrate Scube family consists of three independent members Scube1-3; which encode secreted cell surface-associated membrane glycoproteins that share a domain organization of at least five recognizable motifs and the ability to both homo- and heterodimerize. There is recent biochemical evidence to suggest that Scube2 is directly involved in Hedgehog signaling, acting co-operatively with Dispatched to mediate the release in soluble form of cholesterol and palmitate-modified Hedgehog ligand during long-range activity. Indeed, in the zebrafish myotome, all three Scube proteins can subtly promote Hedgehog signal transduction in a non-cell autonomous manner. In order to further investigate the role of Scube genes during development, we have generated mice with targeted inactivation of Scube3. Despite a dynamic developmental expression pattern, with transcripts present in neuroectoderm, endoderm and endochondral tissues, particularly within the craniofacial region; an absence of Scube3 function results in no overt embryonic phenotype in the mouse. Mutant mice are born at expected Mendelian ratios, are both viable and fertile, and seemingly retain normal Hedgehog signaling activity in craniofacial tissues. These findings suggest that in the mouse, Scube3 is dispensable for normal development; however, they do not exclude the possibility of a co-operative role for Scube3 with other Scube members during embryogenesis or a potential role in adult tissue homeostasis over the long-term.

Molecular cloning, tissue expression pattern, and copy number variation of porcine SCUBE3

“…These results indicate that SCUBE3 is evolutionarily conserved in mammals. This conclusion is consistent with the results of previous studies (Xavier et al, 2013).…”

“…The signal peptide CUB EGF-like domain-containing protein (SCUBE) gene family, which encodes secreted cell-surface proteins, contains 3 members (SCUBE1-3) and is evolutionarily conserved from zebrafish to humans (Wu et al, 2004;Woods and Talbot, 2005;Haworth et al, 2007;Xavier et al, 2013). All three human SCUBE proteins have been found to homodimerize, while SCUBE1 has additionally been shown to heterodimerize with other SCUBE proteins (Wu et al, 2004;Johnson et al, 2012).…”

Scube2 enhances proteolytic Shh processing from the surface of Shh-producing cells

“…By contrast, baseline Shh processing in the absence of external regulators is influenced by the frequency of random protease-substrate encounters, which depends on the concentrations of both proteins. Scube enhancer function thus explains the tissue-restricted, mild phenotypes in you-class zebrafish mutants (Kawakami et al, 2005) and in Scubedeficient mice (Tu et al, 2008;Xavier et al, 2013). Finally, Scube enhancer function is consistent with the lack of Scube orthologs in Drosophila (Tukachinsky et al, 2012).…”

Endothelial SCUBE2 Interacts With VEGFR2 and Regulates VEGF-Induced Angiogenesis

“…vivo vascular phenotypes were not observed in single Scubeknockout mouse strains, [19][20][21] which suggests functional compensation among these SCUBE proteins in the angiogenic endothelium during embryonic development and under normal physiological conditions. Besides being expressed in the normal endothelium, 10,22 SCUBE2 is also highly expressed in hypoxic tumor microvasculature.…”