Fazzari Pietro, Penachioni Junia, Gianola Sara, Rossi Ferdinando, Eickholt Britta J, Maina Flavio, Alexopoulou Lena, Sottile Antonino, Comoglio Paolo Maria, Flavell Richard A, Tamagnone Luca
Institute for Cancer Research and Treatment, University of Torino Medical School, Division of Molecular Oncology, Candiolo, Turin, Italy.
BMC Dev Biol. 2007 May 22;7:55. doi: 10.1186/1471-213X-7-55.
Plexins are a large family of transmembrane receptors for the Semaphorins, known for their role in the assembly of neural circuitry. More recently, Plexins have been implicated in diverse biological functions, including vascular growth, epithelial tissue morphogenesis and tumour development. In particular, PlexinB1, the receptor for Sema4D, has been suggested to play a role in neural development and in tumour angiogenesis, based on in vitro studies. However, the tissue distribution of PlexinB1 has not been extensively studied and the functional relevance of this receptor in vivo still awaits experimental testing. In order to shed light on PlexinB1 function in vivo, we therefore undertook the genomic targeting of the mouse gene to obtain loss of function mutants.
This study shows that PlexinB1 receptor and its putative ligand, Sema4D, have a selective distribution in nervous and epithelial tissues during development and in the adult. PlexinB1 and Sema4D show largely complementary cell distribution in tissues, consistent with the idea that PlexinB1 acts as the receptor for Sema4D in vivo. Interestingly, PlexinB1 is also expressed in certain tissues in the absence of Sema4D, suggesting Sema4D independent activities. High expression of PlexinB1 was found in lung, kidney, liver and cerebellum. Mutant mice lacking expression of semaphorin receptor PlexinB1 are viable and fertile. Although the axon collapsing activity of Sema4D is impaired in PlexinB1 deficient neurons, we could not detect major defects in development, or in adult histology and basic functional parameters of tissues expressing PlexinB1. Moreover, in the absence of PlexinB1 the angiogenic response induced by orthotopically implanted tumours was not affected, suggesting that the expression of this semaphorin receptor in endothelial cells is redundant.
Our expression analysis suggests a multifaceted role of PlexinB1 during mouse development and tissue homeostasis in the adult. Nonetheless, the genetic deletion of PlexinB1 does not result in major developmental defects or clear functional abnormalities. We infer that PlexinB1 plays a redundant role in mouse development and it is not strictly required for tumour induced angiogenesis.
丛状蛋白是一类庞大的跨膜受体，是信号素的受体，以其在神经回路组装中的作用而闻名。最近，丛状蛋白参与了多种生物学功能，包括血管生长、上皮组织形态发生和肿瘤发展。特别是，基于体外研究，信号素4D的受体丛状蛋白B1被认为在神经发育和肿瘤血管生成中发挥作用。然而，丛状蛋白B1的组织分布尚未得到广泛研究，该受体在体内的功能相关性仍有待实验验证。为了阐明丛状蛋白B1在体内的功能，我们对小鼠基因进行了基因靶向，以获得功能缺失突变体。
本研究表明，丛状蛋白B1受体及其假定的配体信号素4D在发育过程中和成年期的神经和上皮组织中具有选择性分布。丛状蛋白B1和信号素4D在组织中显示出很大程度上互补的细胞分布，这与丛状蛋白B1在体内作为信号素4D受体的观点一致。有趣的是，在没有信号素4D的情况下，丛状蛋白B1也在某些组织中表达，表明存在信号素独立的活性。在肺、肾、肝和小脑中发现丛状蛋白B1的高表达。缺乏信号素受体丛状蛋白B1表达的突变小鼠是存活且可育的。尽管在丛状蛋白B1缺陷的神经元中信号素4D的轴突塌陷活性受损，但我们在发育过程中，或在表达丛状蛋白B1的组织的成年组织学和基本功能参数中未检测到主要缺陷。此外，在没有丛状蛋白B1的情况下，原位植入肿瘤诱导的血管生成反应不受影响，这表明该信号素受体在内皮细胞中的表达是多余的。
我们的表达分析表明丛状蛋白B1在小鼠发育和成年组织稳态中具有多方面的作用。尽管如此，丛状蛋白B1的基因缺失并未导致主要的发育缺陷或明显的功能异常。我们推断丛状蛋白B1在小鼠发育中起冗余作用，并且肿瘤诱导的血管生成并不严格需要它。
