The guidance molecule Semaphorin III is expressed in regions of spinal cord and periphery avoided by growing sensory axons

Wright, Douglas E.; White, Fletcher A.; Gerfen, R. W.; Silos‐Santiago, Inmaculada; Snider, William D.

doi:10.1002/cne.903610209

Cited by 154 publications

(125 citation statements)

References 35 publications

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“…Expression studies of Semaphorin III in rat and chicken revealed a developmentally dynamic expression pattern particularly in the nervous system, the heart, and at the borders of developing bones [Wright et al, 1995;Shepherd et al, 1996]. Correct expression pattern of Sema3a is essential for exact innervations of the neurons during embryonic development.…”

Section: Discussionmentioning

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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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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Section: Discussionmentioning

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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“…At this stage, Sema3A is highly expressed and its expression has been shown to correlate with the growth of DRG axons toward their peripheral and central targets (Wright et al, 1995;Giger et al, 1996). Neurons prepared from DRG at this stage die when treated with Sema3A, but death is blocked by high levels of NGF (Ben-Zvi et al, 2006).…”

Section: Semaphorin/plexina3 Signaling Effects On Drg Neuronal Cell Dmentioning

confidence: 99%

The Semaphorin Receptor PlexinA3 Mediates Neuronal Apoptosis during Dorsal Root Ganglia Development

Ben-Zvi¹,

Manor²,

Schachner³

et al. 2008

J. Neurosci.

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Extensive neuronal cell death during development is believed to be due to a limiting supply of neurotrophic factors. In vitro studies suggest that axon guidance molecules directly regulate neuronal survival, raising the possibility that they play a direct role in neuronal cell death in vivo. However, guidance errors may also influence survival indirectly due to loss of target-derived neurotrophic support. The role of guidance molecules in neuronal death in vivo has thus been difficult to decipher. Semaphorin3A, a repulsive guidance cue for sensory neurons, can induce sensory neuron death in vitro. Null mice studies of the Semaphorin3A coreceptors showed that guidance activity is mediated by PlexinA4, but PlexinA3 partially compensates in PlexinA4 Ϫ/Ϫ mice. Here we demonstrate that both Plexins contribute to Sema3A-induced cell death in vitro, albeit in a different hierarchy. PlexinA3 is absolutely required, while PlexinA4 makes a smaller contribution to cell death. We found that PlexinA3 Ϫ/Ϫ mice, which, unlike PlexinA4 Ϫ/Ϫ mice, do not exhibit sensory axon patterning defects, show reduced neuronal apoptosis and an increased number of DRG neurons. Semaphorin3A involvement in neuronal death in vivo was demonstrated by a sensitization experiment using the proapoptotic effector Bax. Our results identify Plexins as mediators of Semaphorin-induced cell death in vitro, and provide the first evidence implicating Semaphorin/Plexin signaling in neuronal survival independent of its role in axon guidance. The results also support the idea that naturally occurring neuronal cell death reflects not only competition for target-derived trophic factors, but also the action of proapoptotic signaling via a Semaphorin/Plexin pathway.

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“…Sema3A is expressed in ventral spinal cord and acts in vitro as a chemorepellent that is selective for TrkA + axons (Behar et al, 1996;Messersmith et al, 1995;Wright et al, 1995). Correspondingly, studies in mice show that loss-of-function of Sema3A or of its co-receptor neuropilin 1 (Nrp1) results in abnormal penetration of TrkA + sensory axons into the ventral spinal cord (Behar et al, 1996;Gu et al, 2003).…”

Section: Introductionmentioning

confidence: 99%

Type III neuregulin 1 regulates pathfinding of sensory axons in the developing spinal cord and periphery

et al. 2011

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SUMMARYSensory axons must develop appropriate connections with both central and peripheral targets. Whereas the peripheral cues have provided a classic model for neuron survival and guidance, less is known about the central cues or the coordination of central and peripheral connectivity. Here we find that type III Nrg1, in addition to its known effect on neuron survival, regulates axon pathfinding. In type III Nrg1 -/-mice, death of TrkA + nociceptive/thermoreceptive neurons was increased, and could be rescued by Bax elimination. In the Bax and type III Nrg1 double mutants, axon pathfinding abnormalities were seen for TrkA + neurons both in cutaneous peripheral targets and in spinal cord central targets. Axon guidance phenotypes in the spinal cord included penetration of axons into ventral regions from which they would normally be repelled by Sema3A. Accordingly, sensory neurons from type III Nrg1 -/-mice were unresponsive to the repellent effects of Sema3A in vitro, which might account, at least in part, for the central projection phenotype, and demonstrates an effect of type III Nrg1 on guidance cue responsiveness in neurons. Moreover, stimulation of type III Nrg1 back-signaling in cultured sensory neurons was found to regulate axonal levels of the Sema3A receptor neuropilin 1. These results reveal a molecular mechanism whereby type III Nrg1 signaling can regulate the responsiveness of neurons to a guidance cue, and show that type III Nrg1 is required for normal sensory neuron survival and axon pathfinding in both central and peripheral targets.

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The guidance molecule Semaphorin III is expressed in regions of spinal cord and periphery avoided by growing sensory axons

Cited by 154 publications

References 35 publications

Biallelic SEMA3A defects cause a novel type of syndromic short stature

Biallelic SEMA3A defects cause a novel type of syndromic short stature

The Semaphorin Receptor PlexinA3 Mediates Neuronal Apoptosis during Dorsal Root Ganglia Development

Type III neuregulin 1 regulates pathfinding of sensory axons in the developing spinal cord and periphery

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