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 28,634 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Semaphorin 3A can inhibit axonal growth and induce neuronal apoptosis following binding to neuropilin-1, with the membrane proximal MAM (meprin, A5, mu) domain in neuropilin-1 playing a key role in the formation of a higher order receptor complex. If functional motifs on semaphorin 3A and/or the MAM domain can be identified, then small-constrained peptides might be developed as antagonists. We have scored peptide pairs for complementary hydropathy and antisense homology to identify a candidate functional motif in the Ig domain of semaphorin 3A, and in the MAM domain of neuropilin-1. Synthetic peptides corresponding to these sequences fully inhibit growth cone collapse induced by semaphorin 3A. A number of smaller peptides derived from the parental sequence also inhibited the response, particularly after they were constrained by a disulfide bond. Finally, we have used an algorithm to design a peptide that is a near-perfect hydropathic complement of the candidate functional site in the MAM domain; this also inhibits the semaphorin 3A response. Thus, an algorithm-driven methodology has led to the identification of three independent semaphorin 3A antagonists. Semaphorin 3F stimulates growth cone collapse following binding to the closest relative to neuropilin-1 in the genome, neuropilin-2. Where tested, the peptides that antagonise semaphorin 3A failed to inhibit the semaphorin 3F response.
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PMID:A complementary peptide approach applied to the design of novel semaphorin/neuropilin antagonists. 1571 68

Secreted semaphorins are a large group of extracellular proteins involved in a variety of processes during development, including neuronal migration and axon guidance. We screened a peptoid combinatorial library to search for semaphorin 3A inhibitors, and identified a peptoid (SICHI: semaphorin Induced chemorepulsion inhibitor) that blocks semaphorin 3A-chemorepulsion and growth-cone collapse in axons at millimolar concentrations. SICHI inhibits the binding of semaphorin 3A to its receptor complex (neuropilin 1/plexin A1) and semaphorin 3A-induced phosphorylation of GSK3. Chemorepulsion induced by semaphorin 3F or netrin 1 is not blocked by SICHI. We also show that SICHI promotes neural regeneration of damaged axons. We suggest that SICHI, a selective inhibitor of semaphorin 3A, is of therapeutic interest for approaches aimed at promoting axonal regeneration and brain repair.
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PMID:A semaphorin 3A inhibitor blocks axonal chemorepulsion and enhances axon regeneration. 1961 21

NrCAM is a neural cell adhesion molecule of the L1 family that has been linked to autism spectrum disorders, a disease spectrum in which abnormal thalamocortical connectivity may contribute to visual processing defects. Here we show that NrCAM interaction with neuropilin-2 (Npn-2) is critical for semaphorin 3F (Sema3F)-induced guidance of thalamocortical axon subpopulations at the ventral telencephalon (VTe), an intermediate target for thalamic axon sorting. Genetic deletion of NrCAM or Npn-2 caused contingents of embryonic thalamic axons to misproject caudally in the VTe. The resultant thalamocortical map of NrCAM-null mutants showed striking mistargeting of motor and somatosensory thalamic axon contingents to the primary visual cortex, but retinogeniculate targeting and segregation were normal. NrCAM formed a molecular complex with Npn-2 in brain and neural cells, and was required for Sema3F-induced growth cone collapse in thalamic neuron cultures, consistent with a vital function for NrCAM in Sema3F-induced axon repulsion. NrCAM-null mice displayed reduced responses to visual evoked potentials recorded from layer IV in the binocular zone of primary visual cortex (V1), particularly when evoked from the ipsilateral eye, indicating abnormal visual acuity and ocularity. These results demonstrate that NrCAM is required for normal maturation of cortical visual acuity, and suggest that the aberrant projection of thalamic motor and somatosensory axons to the visual cortex in NrCAM-null mutant mice impairs cortical functions.
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PMID:NrCAM deletion causes topographic mistargeting of thalamocortical axons to the visual cortex and disrupts visual acuity. 2127 39