Semaphorin 3E and Plexin-D1 Control Vascular Pattern Independently of Neuropilins

Abstract

The development of a patterned vasculature is essential for normal organogenesis. We found that signaling by semaphorin 3E (Sema3E) and its receptor plexin-D1 controls endothelial cell positioning and the patterning of the developing vasculature in the mouse. Sema3E is highly expressed in developing somites, where it acts as a repulsive cue for plexin-D1-expressing endothelial cells of adjacent intersomitic vessels. Sema3E-plexin-D1 signaling did not require neuropilins, which were previously presumed to be obligate Sema3 coreceptors. Moreover, genetic ablation of Sema3E or plexin-D1 but not neuropilin-mediated Sema3 signaling disrupted vascular patterning. These findings reveal an unexpected semaphorin signaling pathway and define a mechanism for controlling vascular patterning.

The brain within the tumor: new roles for axon guidance molecules in cancers

“…On dissociated neurons, Sema3E has either a repulsive action or a growth promoting one that is dosedependent. 31,32 As mentioned before, this protein and its receptor plexin-D1 were recently shown to control angiogenesis during development 23,33,34 and both could exert a similar function in tumors.…”

“…However, more recent data challenge this classical model. 23 During development, Sema3E was found to repel migrating endothelial cells and control vascular patterning in vivo. Surprisingly, in this system Sema3E function is mediated by plexin-D1 and does not require neuropilin-1.…”

Regulation of immune cell responses by semaphorins and their receptors

“…[24][25][26] However, recent reports have suggested that semaphorin receptor usage is more complex than previously thought. For example, Sema3E signals independently of NPs through plexin-D1, 16 while Sema7A uses integrins to exert its functions in both the nervous and immune systems. 27,28 In addition, two molecules unrelated to plexins and NPs, CD72 29 and T-cell immunoglobulin and mucin domaincontaining protein 2 (TIM-2), 30 functionally interact with Sema4D and Sema4A, respectively, in the immune system (Figure 1).…”

“…They were initially identified as repulsive axon guidance molecules that were required to direct neuronal axons to their appropriate targets. 9 More than 20 types of semaphorins have been identified, 10 and they have diverse functions in many physiological process, 11 including cardiogenesis, 12,13 angiogenesis, 14,15 vasculogenesis, 16 tumor metastasis, [17][18][19] osteoclastogenesis 20 and immune regulation. 21,22 In this review, we focus on two functional aspects of semaphorins, their roles in immune cell-cell interactions and immune cell trafficking.…”

Expression of multiple class three semaphorins in the retina and along the path of zebrafish retinal axons

“…Nine plexin molecules (A1-A4, B1-B3, C1, D1), which also contain a conserved SEMA domain, form the functional receptors of Semas (Tamagnone et al, 1999). The secreted class 3 Semas (Sema3A-3H) require a holoreceptor complex consisting of a neuropilin (Nrp1 or Nrp2) and a plexin for activity, with the exception of Sema3E, which only requires a plexin (Gu et al, 2005). The extracellular portion of neuropilin serves as the Sema binding subunit, while the plexin subunit conveys the signal to the cytoplasm (Nakamura et al, 1998).…”