Distinct Roles for Secreted Semaphorin Signaling in Spinal Motor Axon Guidance

Chromosomal microarray testing is commonly used to identify disease causing de novo copy number variants in patients with developmental delay and multiple congenital anomalies. In such a patient we now observed an 150 kb deletion on chromosome 7q21.11 affecting the first exon of the axon guidance molecule gene SEMA3A (sema domain, immunoglobulin domain (Ig), short basic domain, secreted, (semaphorin) 3A). This deletion was inherited from the healthy father, but considering the function of SEMA3A and phenotypic similarity to the knock‐out mice, we still assumed a pathogenic relevance and tested for a recessive second defect. Sequencing of SEMA3A in the patient indeed revealed the de novo in‐frame mutation p.Phe316_Lys317delinsThrSerSerAsnGlu. Cloning of the mutated allele in combination with two informative SNPs confirmed compound heterozygosity in the patient. While the altered protein structure was predicted to be benign, aberrant splicing resulting in a premature stop codon was proven by RT‐PCR to occur in about half of the transcripts from this allele. Expression profiling in human fetal and adult cDNA panels, confirmed a high expression of SEMA3A in all brain regions as well as in adult and fetal heart and fetal skeletal muscle. Normal intellectual development in the patient was surprising but may be explained by the remaining 20% of SEMA3A expression level demonstrated by quantitative RT‐PCR. We therefore report a novel autosomal recessive syndrome characterized by postnatal short stature with relative macrocephaly, camptodactyly, septal heart defect and several minor anomalies caused by biallelic mutations in SEMA3A. © 2013 Wiley Periodicals, Inc.

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“…joint contracture and muscle weakness observed in the patient might well be explained by Sema3a deficiency [Huber et al, 2005;Do et al, 2011].…”

Section: Discussionmentioning

confidence: 73%

“…SEMA3A is also distinctively and differentially expressed in spinal cord motor neurons and its signaling controls the timing of motor axon ingrowth to the limb [Cohen et al, 2005;Huber et al, 2005].…”

Section: Introductionmentioning

confidence: 99%

Biallelic SEMA3A defects cause a novel type of syndromic short stature

Hofmann

Zweier

Sticht

et al. 2013

American J of Med Genetics Pt A

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“…This may be caused by differential binding of these 2 proteins to their Nrp receptors, since Sema3A and Sema3F ligate Nrp-1 and Nrp-2, respectively. 34 In the context of VP, we clearly show that Sema3A and VEGF require Nrp-1 to induce a VP response, since knockdown of Nrp-1 in the endothelium completely abrogated the VP response to both factors ( Figure 4C). However, we could also selectively disrupt VP induced by Sema3A but not VEGF with a specific monoclonal antibody to Nrp-1 ( Figure 4D).…”

Section: Discussionmentioning

confidence: 73%

Semaphorin 3A suppresses VEGF-mediated angiogenesis yet acts as a vascular permeability factor

Acevedo

Barillas

Weis

et al. 2008

Blood

191

213

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Semaphorin 3A (Sema3A), a known inhibitor of axonal sprouting, also alters vascular patterning. Here we show that Sema3A selectively interferes with VEGF-but not bFGF-induced angiogenesis in vivo. Consistent with this, Sema3A disrupted VEGFbut not bFGF-mediated endothelial cell signaling to FAK and Src, key mediators of integrin and growth factor signaling; however, signaling to ERK by either growth factor was unperturbed. Since VEGF is also a vascular permeability (VP) factor, we examined the role of Sema3A on VEGF-mediated VP in mice. Surprisingly, Sema3A not only stimulated VEGF-mediated VP but also potently induced VP in the absence of VEGF. Sema3A-mediated VP was inhibited either in adult mice expressing a conditional deletion of endothelial neuropilin-1 (Nrp-1) or in wild-type mice systemically treated with a functionblocking Nrp-1 antibody. While both Sema3A-and VEGF-induced VP was Nrp-1 dependent, they use distinct downstream effectors since VEGF-but not Sema3A-induced VP required Src kinase signaling. These findings define a novel role for Sema3A both as a selective inhibitor of VEGF-mediated angiogenesis and a potent inducer of VP.

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“…The close proximity of sema3A to axons and its neurite outgrowthinhibitory effect on F11 cells suggest that sema3A contributes to the fasciculation of regenerating neurites through a mechanism of "surround repulsion," similar to what has been observed during development (Huber et al, 2005). Immune histology for sema3A and neurofilament in the human proximal nerve stump and neuroma.…”

Section: Discussionmentioning

confidence: 66%

“…Second, the receptor for sema3A, neuropilin 1 (npn1), is constitutively expressed in motoneurons and sensory neurons of the peripheral nerve Lindholm et al, 2004) and adult sensory neurons remain sensitive to sema3A (Reza et al, 1999;Tang et al, 2004). Finally, in the developing brachial plexus, sema3A and sema3F coordinate the timing and fasciculation of motor axon growth and determine the dorsoventral organization of motor axon projections (Huber et al, 2005).…”

Section: Introductionmentioning

confidence: 99%

Human Neuroma Contains Increased Levels of Semaphorin 3A, Which Surrounds Nerve Fibers and Reduces Neurite ExtensionIn Vitro

Tannemaat

Korecka²,

Ehlert³

et al. 2007

J. Neurosci.

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Neuroma formation after peripheral nerve injury is detrimental to functional recovery and is therefore a significant clinical problem. The molecular basis for this phenomenon is not fully understood. Here, we show that the expression of the chemorepulsive protein semaphorin 3A (sema3A), but not semaphorin 3F, is increased in human neuroma tissue that has formed in severe obstetric brachial plexus lesions. Sema3A is produced by fibroblasts in the epineurial space and appears to be secreted into the extracellular matrix. It surrounds fascicles, minifascicles, or single axons, suggesting a role in fasciculation and inhibition of neurite outgrowth. Lentiviral vector-mediated knock-down of Neuropilin 1, the receptor for sema3A, leads to increased neurite outgrowth of F11 cells cultured on neuroma tissue, but not of F11 cells cultured on normal nerve tissue. These findings demonstrate the putative inhibitory role of sema3A in human neuroma tissue. Our observations are the first demonstration of the expression of sema3A in human neural scar tissue and support a role for this protein in the inhibition of axonal regeneration in injured human peripheral nerves. These findings contribute to the understanding of the outgrowth inhibitory properties of neuroma tissue.

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Distinct Roles for Secreted Semaphorin Signaling in Spinal Motor Axon Guidance

Cited by 87 publications

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Biallelic SEMA3A defects cause a novel type of syndromic short stature

Biallelic SEMA3A defects cause a novel type of syndromic short stature

Semaphorin 3A suppresses VEGF-mediated angiogenesis yet acts as a vascular permeability factor

Human Neuroma Contains Increased Levels of Semaphorin 3A, Which Surrounds Nerve Fibers and Reduces Neurite ExtensionIn Vitro

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