Alternative titles; symbols
HGNC Approved Gene Symbol: PSD
Cytogenetic location: 10q24.32 Genomic coordinates (GRCh38): 10:102,402,619-102,419,946 (from NCBI)
PSD is a guanine nucleotide exchange factor (GEF) for ARF6 (619948) in brain. PSD is involved in cytoskeletal remodeling (Sironi et al., 2009) and regulation of polarized transport and axon regeneration of neurons (Eva et al., 2017).
Perletti et al. (1997) isolated a cDNA of 4,307 bp from an adult human brain cDNA library, which encodes a putative protein of 645 amino acids with a predicted molecular mass of 71 kD. Database homology searches indicated that the novel gene codes for a putative protein containing 2 discrete domains with significant homology to the Sec7 and pleckstrin-homology (PH) domains, respectively. They used the gene symbol PSD for 'pleckstrin-Sec7 domains.' Northern blot analysis of a panel of RNAs from normal human tissues using the PSD cDNA as probe revealed the presence of 3 tissue-specific transcripts of approximately 4.3, 2.3, and 1.8 kb; the longest transcript was expressed only in brain. The data suggested that the PSD protein may belong to a family of proteins that contain Sec7 and PH domains and are thought to be involved in signaling transduction processes. Other human proteins in this family include cytohesin-1 (182115) and ARNO (602488).
Derrien et al. (2002) reported that PSD, which they called EFA6A, is 63% identical to EFA6B (PSD4; 614442) and contains a Sec7 domain adjacent to a PH domain, followed by a C-terminal coiled-coil motif. Northern blot analysis showed that EFA6A expression was largely restricted to brain, with a smaller transcript expressed in small intestine, colon, and ovary. Immunofluorescence microscopy demonstrated punctate cell surface expression of ARF6 and EFA6A, like EFA6B, in transfected baby hamster kidney cells. Both EFA6 proteins also colocalized with F-actin (see 102610).
By in situ hybridization and Northern blot analyses, Sakagami et al. (2004) showed that Efa6a mRNA displayed somatodendritic localization and a developmental expression pattern in rat hippocampus.
Sironi et al. (2009) cloned 2 splice variants of mouse Efa6a. The longer variant, Efa6a, encodes a 1,025-amino acid isoform containing 2 proline-rich sequences, a Sec7 domain, a PH domain, and 2 putative coiled-coil motifs in the C-terminal region. The shorter variant, Efa6as, encodes a 393-amino acid isoform with a unique N-terminal stretch of 66 amino acids followed by 327 amino acids identical to Efa6a, encompassing the PH domain and the C-terminal coiled-coil regions. Database analysis revealed an EFA6A short isoform in human and its conservation in vertebrates. Efa6a and Efa6as were both expressed in mouse brain, but they had a distinct temporal regulation during development. Efa6a expression peaked at postnatal days 4 through, 8 and it was downregulated in adult, whereas highest expression of Efa6as was detected in adult brain. Immunofluorescence assays showed that both Efa6a and Efa6as predominantly localized at the plasma membrane when expressed in HeLa cells.
Using immunofluorescence assays, Eva et al. (2017) showed that Efa6 localized to the axon initial segment in rat cortical neurons, with lower expression throughout dendrites and the cell body.
Derrien et al. (2002) found that recombinant EFA6A stimulated nucleotide exchange on myristoylated ARF6, with only low activity on ARF1 (103180). The C-terminal region was involved in microvilli lengthening. Derrien et al. (2002) concluded that EFA6 family guanine exchange factors are modular proteins that work through the coordinated action of the catalytic Sec7 domain to promote ARF6 activation, through the PH domain to regulate association with specific subdomains of the plasma membrane, and through the C-terminal region to control actin cytoskeletal reorganization.
Sakagami et al. (2004) found that expression of an inactive Efa6a mutant induced dendritic formation in rat primary hippocampal neurons.
Sironi et al. (2009) demonstrated that expression of mouse Efa6a or Efa6as induced cytoskeletal remodeling in HeLa cells. However, morphologic changes resulting from the remodeling were distinct between Efa6a and Efa6as, as Efa6a promoted formation of membrane ruffles and loss of stress fibers, and Efa6as induced cell elongation. The common C-terminal region of the 2 isoforms was essential for remodeling. Expression analysis in various neuronal cells revealed functional distinction between the isoforms. Arf6 and Rho GTPase activity were involved in Efa6a function, but not in Efa6as function, as Efa6as did not modulate the GEF activity of Arf6. Coexpression of Efa6a and Efa6as in primary cortical neurons suggested possible involvement of the balance between Efa6a and Efa6as expression levels in the regulation of neuronal morphogenesis.
By knockdown analysis, Eva et al. (2017) showed that Efa6 was involved in Arf6 activation throughout mature axons of rat neurons, despite its localization in the axon initial segment. Consistent with the absence of a microtubule-binding domain, Efa6 did not regulate axonal microtubule dynamics. Integrins are restricted to dendrites in differentiated neurons and display a polarized distribution due to Arf6-regulated direction of axonal integrin transport. Efa6 directed integrins away from axons, as loss of Eef6 reversed integrin transport direction and increased integrin levels throughout the axon in neurons. Efa6 directed Rab11 (605570) endosomes, which transport axonal integrins, away from neuronal axons, as depletion of Efa6 promoted axon transport of Rab11 without altering global axon transport. Moreover, depleting Efa6 enhanced the regenerative capacity of differentiated cortical neurons, confirming that Rab11, integrins, and reduced Arf6 activity are beneficial for axon growth. Further analysis showed that Efa6 activated Arf6 and that the activation state of Arf6 regulated axon regeneration in neurons by controlling exclusion of Rab11 vesicles and their contents, such as integrins, from axons.
Perletti et al. (1997) identified the PSD gene on chromosome 10q24, contiguous to the 3-prime end of the NFKB2 gene (164012) in a tail-to-tail arrangement.
Gross (2012) mapped the PSD gene to chromosome 10q24.32 based on an alignment of the PSD sequence (GenBank BC142689) with the genomic sequence (GRCh37).
Derrien, V., Couillault, C., Franco, M., Martineau, S., Montcourrier, P., Houlgatte, R., Chavrier, P. A conserved C-terminal domain of EFA6-family ARF6-guanine nucleotide exchange factors induces lengthening of microvilli-like membrane protrusions. J. Cell Sci. 115: 2867-2879, 2002. [PubMed: 12082148] [Full Text: https://doi.org/10.1242/jcs.115.14.2867]
Eva, R., Koseki, H., Kanamarlapudi, V., Fawcett, J. W. EFA6 regulates selective polarised transport and axon regeneration from the axon initial segment. J. Cell Sci. 130: 3663-3675, 2017. [PubMed: 28935671] [Full Text: https://doi.org/10.1242/jcs.207423]
Gross, M. B. Personal Communication. Baltimore, Md. 1/24/2012.
Perletti, L., Talarico, D., Trecca, D., Ronchetti, D., Fracchiolla, N. S., Maiolo, A. T., Neri, A. Identification of a novel gene, PSD, adjacent to NFKB2/lyt-10, which contains Sec7 and pleckstrin-homology domains. Genomics 46: 251-259, 1997. [PubMed: 9417912] [Full Text: https://doi.org/10.1006/geno.1997.5022]
Sakagami, H., Matsuya, S., Nishimura, H., Suzuki, R., Kondo, H. Somatodendritic localization of the mRNA for EFA6A, a guanine nucleotide exchange protein for ARF6, in rat hippocampus and its involvement in dendritic formation. Europ. J. Neurosci. 19: 863-870, 2004. [PubMed: 15009133] [Full Text: https://doi.org/10.1111/j.0953-816x.2004.03195.x]
Sironi, C., Teesalu, T., Muggia, A., Fontana, G., Marino, F., Savaresi, S., Talarico, D. EFA6A encodes two isoforms with distinct biological activities in neuronal cells. J. Cell Sci. 122: 2108-2118, 2009. [PubMed: 19494129] [Full Text: https://doi.org/10.1242/jcs.042325]