| 2016 |
GPM6a-induced neuronal filopodium formation requires a signaling pathway involving coronin-1a (Coro1a), Rac1, and p21-activated kinase 1 (Pak1). Coro1a associates with Gpm6a (shown by co-immunoprecipitation), co-localizes with Gpm6a in F-actin-enriched regions of hippocampal neurons, and co-immunoprecipitates with Rac1 together with Gpm6a. Dominant-negative Coro1a or Coro1a siRNA knockdown interferes with Gpm6a-induced filopodium formation. Pharmacological inhibition of Rac1 or co-expression with GDP-bound (inactive) Rac1 reduces filopodium formation; Gpm6a also facilitates Rac1 membrane recruitment. Kinase activity of Pak1 is required downstream of Rac1 for Gpm6a-induced filopodium formation. |
Co-immunoprecipitation, immunofluorescence microscopy, dominant-negative expression, siRNA knockdown, pharmacological inhibition (Rac1 inhibitor), GDP-bound Rac1 co-expression |
Journal of neurochemistry |
High |
26809475
|
| 2018 |
The C-terminal cytosolic tail of Gpm6a is required for filopodium formation; specifically residues K250, K255, and E258 are essential. Deletion of the C-terminus (but not N-terminus) abolishes filopodium induction and diminishes Gpm6a association with clathrin, implicating clathrin-mediated trafficking. Both truncation mutants reduce surface levels of Gpm6a without altering total expression. Alanine substitution of K255 and E258 also reduces total protein, and all three key residues are predicted as part of sorting signals of transmembrane proteins. |
Alanine scanning mutagenesis, truncation mutants, immunofluorescence microscopy, flow cytometry (cell surface quantification), colocalization assay with clathrin |
Frontiers in molecular neuroscience |
High |
30233315
|
| 2024 |
Gpm6a is palmitoylated by the DHHC palmitoyltransferases Zdhhc1 and Zdhhc2 at Cys17, Cys18, and Cys246. This palmitoylation is required for Gpm6a to mediate lipid raft formation, which in turn stabilizes the Procr (protein C receptor) protein in adult mammary stem cells. Gpm6a knockout in mice reduces Procr protein stability and impairs mammary stem cell activity and postnatal mammary development. |
Gpm6a knockout mouse model, site-directed mutagenesis of palmitoylation sites, lipid raft fractionation, protein stability assays, in vivo mammary development analysis |
Cell reports |
High |
39321020
|
| 2017 |
HDAC5 inhibits neurite elongation at least partially via a MEF2C/GPM6A signaling pathway. GPM6A (M6a) is a direct target gene of the HDAC5-regulated transcription factor MEF2C. miR-124 and miR-9 repress HDAC5, thereby de-repressing MEF2C and increasing GPM6A expression to promote neurite development in differentiated P19 cells and primary neurons. |
miRNA overexpression, HDAC5 overexpression/knockdown in P19 cells and primary neurons, reporter assays for MEF2C-GPM6A transcriptional regulation, neurite length measurement |
Journal of cellular physiology |
Medium |
28332716
|
| 2014 |
GPM6A/M6 dosage is critical for cognitive function and associates with cholesterol homeostasis. In a Drosophila model, knockdown of M6 (the sole PLP family member in flies) causes wing malformation and lethality; overexpression or loss of M6 in neurons impairs long-term memory. Phenotypes including filopodium-like protrusions in patient-derived lymphoblastoid cells (with GPM6A duplication) and Drosophila M6 knockdown phenotypes are alleviated by cholesterol supplementation, supporting a functional link between GPM6A and cholesterol-rich lipid rafts. |
Drosophila M6 knockdown/overexpression (wing and neuron-specific), long-term memory assay (courtship conditioning), cholesterol supplementation rescue, patient-derived lymphoblastoid cell analysis |
Human mutation |
Medium |
25224183
|
| 2024 |
GPM6a interacts with ICAM5 via both cis and trans interactions mediated by GPM6a's extracellular domains. Co-immunoprecipitation and cell aggregation assays in HEK293 cells confirmed physical interaction. In hippocampal neurons, endogenous GPM6a clusters co-localize with ICAM5 clusters in the dendritic shaft. Co-overexpression of GPM6a and ICAM5 additively enhances neurite length, neurite number (in N2a cells), and filopodium formation in neurons. |
Co-immunoprecipitation, cell aggregation assay, immunofluorescence co-localization, overexpression in N2a cells and hippocampal neurons |
Journal of neurochemistry |
Medium |
39352694
|
| 2025 |
Non-synonymous SNPs (T71P, T76I, M154V, F156Y, R163Q, T210N) within GPM6a's extracellular domains impair GPM6a-induced neuronal plasticity (neurite outgrowth, filopodia formation) without affecting expression level, folding, or general membrane localization, but alter membrane distribution and, in at least one variant, disrupt GPM6a oligomerization. The extracellular domain variants reduce GPM6a's ability to induce cell aggregation, establishing that homophilic cis interactions through extracellular domains are essential for GPM6a function. |
Site-directed mutagenesis of nsSNPs, neuronal culture assays (neurite/filopodia quantification), cell aggregation assay, flow cytometry for surface expression |
Biochimica et biophysica acta. Molecular cell research |
Medium |
39938689
|
| 2009 |
GPM6A expression level directly modulates the differentiation of human ES cell-derived neurons and neuronal migration. Overexpression of GPM6A in human ES cells increases neuroectodermal gene expression, neural stem cell numbers, and production of cholinergic, catecholaminergic, and GABAergic neurons, and enhances neuronal migration. Suppression of GPM6A by shRNA has the opposite effects. |
shRNA knockdown, overexpression in human ES cells, real-time PCR, immunocytochemistry, neuronal migration assays |
Stem cells and development |
Medium |
19298174
|
| 2008 |
GPM6A is required for neuronal differentiation of mouse ES cells. shRNA-mediated knockdown of GPM6A in mouse ES cells markedly reduces expression of neuroectodermal genes and decreases the number of neural stem cells and differentiated neurons (cholinergic, catecholaminergic, and GABAergic). |
shRNA knockdown in mouse ES cells, real-time PCR, immunocytochemistry |
Stem cells and development |
Medium |
18522499
|
| 2023 |
GPM6a is required for neurite elongation in rat dorsal root ganglion (DRG) neurons of the peripheral nervous system. Endogenous GPM6a is present on DRG neuron cell surfaces throughout development, and functional experiments (knockdown in vitro) demonstrate that GPM6a is necessary for DRG neurite elongation. |
RNA-seq dataset analysis, immunochemistry of DRG cultures, loss-of-function experiments in dissociated DRG neurons |
Biomolecules |
Medium |
37189342
|
| 2023 |
Chronic stress in rats down-regulates hippocampal Gpm6a mRNA, and this is linked to miR-124-3p-mediated modulation of Hdac5 and Mef2c expression. miR-124 overexpression in hippocampal neurons in vitro increases neuronal arborization, Gpm6a, and Mef2c expression while decreasing Hdac5. BDNF treatment elevates miR-124-3p and Gpm6a/Mef2c mRNA while reducing Hdac5. |
Chronic restraint stress rat model, qPCR, miR-124 overexpression in hippocampal neurons, BDNF treatment, Sholl analysis of neuronal arborization |
Journal of neurochemistry |
Medium |
36943192
|
| 2014 |
GPM6A (isoform 3) overexpression in NIH/3T3 cells alters actin and microtubule networks and induces formation of long filopodia-like protrusions. GPM6A overexpression also confers anchorage-independent growth and enhanced proliferation, suggesting a role in cytoskeletal remodeling. |
Overexpression in NIH/3T3 cells, confocal/indirect immunofluorescence microscopy, soft agar colony formation assay, flow cytometry |
Cellular oncology |
Low |
24916915
|
| 1996 |
The human GPM6A gene encodes a 278-amino-acid transmembrane membrane glycoprotein with specific expression in human brain, and maps to chromosome 4q33→q34. |
cDNA cloning, Northern blot, radiation hybrid mapping |
Cytogenetics and cell genetics |
Low |
8893821
|