ASTN1 (astrotactin 1) is a large neuronal membrane protein with two transmembrane helices and an extracellular region carrying three EGF-like repeats and a fibronectin type III domain. It is expressed in postmitotic neuronal precursors of laminated brain regions and acts as a neuronal ligand for adhesion to radial and Bergmann glial fibres during glial-guided migration. Its paralog ASTN2 forms a complex with it and controls its surface level. ASTN1 is endocytosed and recycled to the front of the leading process, which may coordinate making and releasing glial contacts as the neuron moves. Astn1-null mice have slowed granule cell migration, small cerebella and poor motor coordination. Bi-allelic ASTN1 variants in humans cause neurodevelopmental disorders with variable cortical and cerebellar malformations.
| GO Term | Evidence | Action | Reason |
|---|---|---|---|
| GO:0001764 neuron migration | IBA GO_REF:0000033 | ACCEPT | Summary: Neuron migration (IBA). Astrotactin is the neuronal ligand for glial-guided migration. Antibody blockade arrests granule-cell migration on astroglial fibres, Astn1-null mice have slowed migration and small cerebella, and bi-allelic human ASTN1 variants cause neuronal migration disorders. Core process. Reason: [PMID:8602532 "Fab fragments of antibodies to a recombinant astrotactin peptide blocked migration of cerebellar granule neurons in vitro along astroglial fibers."] [PMID:11861479 "In vitro and in vivo cerebellar granule cell assays show a decrease in neuron-glial binding, a reduction in migration rates and abnormal development of Purkinje cells."] [PMID:41544630 "Here, we describe eighteen individuals with NDDs from twelve unrelated families with bi-allelic, ultra-rare, predicted damaging variants in ASTN1 and one individual with heterozygous variants in both ASTN1 and ASTN2 ."] [PMID:41544630 "Brain malformations appreciated were varied and included mild cerebral atrophy, polymicrogyria, lissencephaly, colpocephaly, malformation of the hippocampus, bilateral periventricular hyperintensities, and dysgenesis of the corpus callosum and cerebellum."] Propagation Review Root cause: NO FAILURE CORE Sources checked: PANTHER:PTN000422025 SUPPORTS TRANSFER Node seeded by mouse Astn1 experimental data (PMID:8602532, PMID:11861479); human ASTN1 is an orthologous member. Supporting Evidence: PMID:8602532 Fab fragments of antibodies to a recombinant astrotactin peptide blocked migration of cerebellar granule neurons in vitro along astroglial fibers. PMID:11861479 In vitro and in vivo cerebellar granule cell assays show a decrease in neuron-glial binding, a reduction in migration rates and abnormal development of Purkinje cells. PMID:41544630 Here, we describe eighteen individuals with NDDs from twelve unrelated families with bi-allelic, ultra-rare, predicted damaging variants in ASTN1 and one individual with heterozygous variants in both ASTN1 and ASTN2 . PMID:41544630 Brain malformations appreciated were varied and included mild cerebral atrophy, polymicrogyria, lissencephaly, colpocephaly, malformation of the hippocampus, bilateral periventricular hyperintensities, and dysgenesis of the corpus callosum and cerebellum. |
| GO:0001764 neuron migration | IEA GO_REF:0000002 | ACCEPT | Summary: Neuron migration (IEA, InterPro IPR026995 Astrotactin). The InterPro family is specific to the astrotactins, both of which act in glial-guided neuronal migration. Antibody blockade and the mouse knockout establish the role for ASTN1, and bi-allelic human variants cause migration disorders. Accepted. Reason: [file:human/ASTN1/ASTN1-uniprot.txt "DR InterPro; IPR026995; Astrotactin."] [PMID:8602532 "Fab fragments of antibodies to a recombinant astrotactin peptide blocked migration of cerebellar granule neurons in vitro along astroglial fibers."] [PMID:11861479 "In vitro and in vivo cerebellar granule cell assays show a decrease in neuron-glial binding, a reduction in migration rates and abnormal development of Purkinje cells."] [PMID:41544630 "Here, we describe eighteen individuals with NDDs from twelve unrelated families with bi-allelic, ultra-rare, predicted damaging variants in ASTN1 and one individual with heterozygous variants in both ASTN1 and ASTN2 ."] Supporting Evidence: file:human/ASTN1/ASTN1-uniprot.txt DR InterPro; IPR026995; Astrotactin. PMID:8602532 Fab fragments of antibodies to a recombinant astrotactin peptide blocked migration of cerebellar granule neurons in vitro along astroglial fibers. PMID:11861479 In vitro and in vivo cerebellar granule cell assays show a decrease in neuron-glial binding, a reduction in migration rates and abnormal development of Purkinje cells. PMID:41544630 Here, we describe eighteen individuals with NDDs from twelve unrelated families with bi-allelic, ultra-rare, predicted damaging variants in ASTN1 and one individual with heterozygous variants in both ASTN1 and ASTN2 . |
| GO:0005768 endosome | IBA GO_REF:0000033 | KEEP AS NON CORE | Summary: Endosome (IBA). ASTN1 is found in a subset of RhoB-positive endosomes, and its surface level is controlled by clathrin-mediated endocytosis. This endocytic recycling is thought to help release glial adhesions as the neuron moves. Endosomes are a trafficking compartment, though: ASTN1's adhesion activity is at the cell surface. The location is correct, but the IBA's is_active_in qualifier overstates it. Kept as non-core, consistent with the clathrin-coated vesicle row. Reason: [PMID:20573900 "In single, optical sections of fixed cells, both ASTN1 and ASTN2 are expressed in a subset of RhoB-positive endosomes, as well as in vesicles that are not RhoB positive"] [PMID:20573900 "These findings support the idea that surface localization of ASTN1-Venus is regulated by clathrin-mediated receptor endocytosis."] [PMID:20573900 "Together, these findings suggest that ASTN2 regulates the levels of ASTN1 in the plasma membrane and that the release of neuronal adhesions to the glial fiber during neuronal locomotion involves the intracellular trafficking of ASTN1."] [PMID:20573900 "ASTN1 is exposed on the cell surface and, as demonstrated previously ( Stitt and Hatten, 1990 ; Zheng et al., 1996 ), provides a ligand for neuron-glial adhesion during migration."] Propagation Review Root cause: NO FAILURE NON CORE Sources checked: PANTHER:PTN000422025 SUPPORTS TRANSFER Node seeded by mouse Astn1 IDA (PMID:20573900). The location is correct, but is_active_in places the activity in a trafficking compartment rather than at the surface. Supporting Evidence: PMID:20573900 In single, optical sections of fixed cells, both ASTN1 and ASTN2 are expressed in a subset of RhoB-positive endosomes, as well as in vesicles that are not RhoB positive PMID:20573900 These findings support the idea that surface localization of ASTN1-Venus is regulated by clathrin-mediated receptor endocytosis. PMID:20573900 Together, these findings suggest that ASTN2 regulates the levels of ASTN1 in the plasma membrane and that the release of neuronal adhesions to the glial fiber during neuronal locomotion involves the intracellular trafficking of ASTN1. PMID:20573900 ASTN1 is exposed on the cell surface and, as demonstrated previously ( Stitt and Hatten, 1990 ; Zheng et al., 1996 ), provides a ligand for neuron-glial adhesion during migration. |
| GO:0005768 endosome | IEA GO_REF:0000120 | KEEP AS NON CORE | Summary: Endosome (IEA (mouse ortholog projection)). ASTN1 is found in a subset of RhoB-positive endosomes, and its surface level is controlled by clathrin-mediated endocytosis. This endocytic recycling is thought to help release glial adhesions as the neuron moves. Endosomes are a trafficking compartment, though: ASTN1's adhesion activity is at the cell surface. The location is correct, but the IBA's is_active_in qualifier overstates it. Kept as non-core, consistent with the clathrin-coated vesicle row. Reason: [PMID:20573900 "In single, optical sections of fixed cells, both ASTN1 and ASTN2 are expressed in a subset of RhoB-positive endosomes, as well as in vesicles that are not RhoB positive"] [PMID:20573900 "These findings support the idea that surface localization of ASTN1-Venus is regulated by clathrin-mediated receptor endocytosis."] [PMID:20573900 "Together, these findings suggest that ASTN2 regulates the levels of ASTN1 in the plasma membrane and that the release of neuronal adhesions to the glial fiber during neuronal locomotion involves the intracellular trafficking of ASTN1."] [PMID:20573900 "ASTN1 is exposed on the cell surface and, as demonstrated previously ( Stitt and Hatten, 1990 ; Zheng et al., 1996 ), provides a ligand for neuron-glial adhesion during migration."] Supporting Evidence: PMID:20573900 In single, optical sections of fixed cells, both ASTN1 and ASTN2 are expressed in a subset of RhoB-positive endosomes, as well as in vesicles that are not RhoB positive PMID:20573900 These findings support the idea that surface localization of ASTN1-Venus is regulated by clathrin-mediated receptor endocytosis. PMID:20573900 Together, these findings suggest that ASTN2 regulates the levels of ASTN1 in the plasma membrane and that the release of neuronal adhesions to the glial fiber during neuronal locomotion involves the intracellular trafficking of ASTN1. PMID:20573900 ASTN1 is exposed on the cell surface and, as demonstrated previously ( Stitt and Hatten, 1990 ; Zheng et al., 1996 ), provides a ligand for neuron-glial adhesion during migration. |
| GO:0005886 plasma membrane | IEA GO_REF:0000044 | ACCEPT | Summary: Plasma membrane (IEA). Live-cell immunostaining shows ASTN1 at the cell surface, ASTN2 lowers its surface level fourfold by flow cytometry, and its role as a neuron-glia adhesion ligand is exercised there. Core location. Reason: [PMID:20573900 "Live cell immunostaining revealed a discrete, speckled cell surface-staining pattern in the cells cotransfected with ASTN1-Venus and Myc control vectors ( Fig. 8 A3 ), demonstrating that the C terminus of ASTN1 is exposed on the cell surface."] [PMID:20573900 "Biochemical and flow cytometry experiments show that ASTN2 forms a complex with ASTN1 and regulates surface expression of ASTN1."] [PMID:20573900 "ASTN1 is exposed on the cell surface and, as demonstrated previously ( Stitt and Hatten, 1990 ; Zheng et al., 1996 ), provides a ligand for neuron-glial adhesion during migration."] Supporting Evidence: PMID:20573900 Live cell immunostaining revealed a discrete, speckled cell surface-staining pattern in the cells cotransfected with ASTN1-Venus and Myc control vectors ( Fig. 8 A3 ), demonstrating that the C terminus of ASTN1 is exposed on the cell surface. PMID:20573900 Biochemical and flow cytometry experiments show that ASTN2 forms a complex with ASTN1 and regulates surface expression of ASTN1. PMID:20573900 ASTN1 is exposed on the cell surface and, as demonstrated previously ( Stitt and Hatten, 1990 ; Zheng et al., 1996 ), provides a ligand for neuron-glial adhesion during migration. |
| GO:0007158 neuron cell-cell adhesion | IBA GO_REF:0000033 | ACCEPT | Summary: Neuron cell-cell adhesion (IBA). The term covers attachment of a neuron to another cell, which includes glia. ASTN1 mediates neuron-glia binding: expressing astrotactin in 3T3 cells confers glial binding, and Astn1-null granule cells bind glia less. Core process. Reason: [PMID:8602532 "Transfection of astrotactin complementary DNA into 3T3 cells indicated that astrotactin acts as a ligand for neuron-glia binding during neuronal migration."] [PMID:11861479 "In vitro and in vivo cerebellar granule cell assays show a decrease in neuron-glial binding, a reduction in migration rates and abnormal development of Purkinje cells."] Propagation Review Root cause: NO FAILURE CORE Sources checked: PANTHER:PTN000422025 SUPPORTS TRANSFER Node seeded by mouse Astn1 IDA (PMID:8602532). Supporting Evidence: PMID:8602532 Transfection of astrotactin complementary DNA into 3T3 cells indicated that astrotactin acts as a ligand for neuron-glia binding during neuronal migration. PMID:11861479 In vitro and in vivo cerebellar granule cell assays show a decrease in neuron-glial binding, a reduction in migration rates and abnormal development of Purkinje cells. |
| GO:0009897 external side of plasma membrane | IEA GO_REF:0000107 | ACCEPT | Summary: External side of plasma membrane (IEA, mouse ortholog projection). The large ASTN1 C-terminal region (403-1302) carrying the EGF-like and fibronectin type III domains is predicted to be extracellular. Live staining of a C-terminally tagged ASTN1 confirms that the C terminus is exposed on the cell surface. The adhesive ectodomain therefore faces outward. Accepted as consistent with the topology. Reason: [file:human/ASTN1/ASTN1-uniprot.txt "FT TOPO_DOM 403..1302"] [PMID:20573900 "Live cell immunostaining revealed a discrete, speckled cell surface-staining pattern in the cells cotransfected with ASTN1-Venus and Myc control vectors ( Fig. 8 A3 ), demonstrating that the C terminus of ASTN1 is exposed on the cell surface."] Supporting Evidence: file:human/ASTN1/ASTN1-uniprot.txt FT TOPO_DOM 403..1302 PMID:20573900 Live cell immunostaining revealed a discrete, speckled cell surface-staining pattern in the cells cotransfected with ASTN1-Venus and Myc control vectors ( Fig. 8 A3 ), demonstrating that the C terminus of ASTN1 is exposed on the cell surface. |
| GO:0016020 membrane | IBA GO_REF:0000033 | ACCEPT | Summary: Membrane (IBA). Broad parent of the plasma membrane annotation; ASTN1 has two predicted transmembrane helices. Correct but uninformative; accepted. Reason: [file:human/ASTN1/ASTN1-uniprot.txt "FT TRANSMEM 384..402"] [file:human/ASTN1/ASTN1-uniprot.txt "CC -!- SUBCELLULAR LOCATION: Cell membrane {ECO:0000250|UniProtKB:Q61137};"] Propagation Review Root cause: NO FAILURE CORE Sources checked: PANTHER:PTN000422025 SUPPORTS TRANSFER Node seeded by mouse Astn1 IDA (PMID:20573900). Supporting Evidence: file:human/ASTN1/ASTN1-uniprot.txt FT TRANSMEM 384..402 file:human/ASTN1/ASTN1-uniprot.txt CC -!- SUBCELLULAR LOCATION: Cell membrane {ECO:0000250|UniProtKB:Q61137}; |
| GO:0016020 membrane | IEA GO_REF:0000107 | ACCEPT | Summary: Membrane (IEA (mouse ortholog projection)). Broad parent of the plasma membrane annotation; ASTN1 has two predicted transmembrane helices. Correct but uninformative; accepted. Reason: [file:human/ASTN1/ASTN1-uniprot.txt "FT TRANSMEM 384..402"] [file:human/ASTN1/ASTN1-uniprot.txt "CC -!- SUBCELLULAR LOCATION: Cell membrane {ECO:0000250|UniProtKB:Q61137};"] Supporting Evidence: file:human/ASTN1/ASTN1-uniprot.txt FT TRANSMEM 384..402 file:human/ASTN1/ASTN1-uniprot.txt CC -!- SUBCELLULAR LOCATION: Cell membrane {ECO:0000250|UniProtKB:Q61137}; |
| GO:0030136 clathrin-coated vesicle | IEA GO_REF:0000044 | KEEP AS NON CORE | Summary: Clathrin-coated vesicle (IEA, UniProt subcellular location). ASTN1 colocalizes with clathrin light chain in migrating granule cells and is internalized by clathrin-mediated endocytosis. Like the endosome rows, this is a transit compartment in ASTN1's recycling route rather than where its adhesion activity occurs. Kept as non-core. Reason: [PMID:20573900 "By confocal microscopy, ASTN1 and ASTN2 colocalize with Clathrin light chain-Venus in migrating cerebellar granule cells"] [PMID:20573900 "These findings support the idea that surface localization of ASTN1-Venus is regulated by clathrin-mediated receptor endocytosis."] [file:human/ASTN1/ASTN1-uniprot.txt "CC neurons. Is internalized from the membrane via clathrin-coated vesicles"] Supporting Evidence: PMID:20573900 By confocal microscopy, ASTN1 and ASTN2 colocalize with Clathrin light chain-Venus in migrating cerebellar granule cells PMID:20573900 These findings support the idea that surface localization of ASTN1-Venus is regulated by clathrin-mediated receptor endocytosis. file:human/ASTN1/ASTN1-uniprot.txt CC neurons. Is internalized from the membrane via clathrin-coated vesicles |
| GO:0043204 perikaryon | IEA GO_REF:0000044 | KEEP AS NON CORE | Summary: Perikaryon (IEA, UniProt subcellular location from mouse). In migrating neurons ASTN1 sits near the anterior pole of the soma and at the base of the leading process. Correct but descriptive; kept as non-core. Reason: [file:human/ASTN1/ASTN1-uniprot.txt "CC Multi-pass membrane protein {ECO:0000250|UniProtKB:Q61137}. Perikaryon"] [file:human/ASTN1/ASTN1-uniprot.txt "CC anterior pole and at the base of the leading process in migrating"] [PMID:20573900 "Live imaging of Venus-tagged ASTN1 in migrating cerebellar granule cells reveals the intracellular trafficking of ASTN1-Venus, with ASTN1-Venus accumulating in the forward aspect of the leading process where new sites of adhesion will form."] Supporting Evidence: file:human/ASTN1/ASTN1-uniprot.txt CC Multi-pass membrane protein {ECO:0000250|UniProtKB:Q61137}. Perikaryon file:human/ASTN1/ASTN1-uniprot.txt CC anterior pole and at the base of the leading process in migrating PMID:20573900 Live imaging of Venus-tagged ASTN1 in migrating cerebellar granule cells reveals the intracellular trafficking of ASTN1-Venus, with ASTN1-Venus accumulating in the forward aspect of the leading process where new sites of adhesion will form. |
| GO:0098632 cell-cell adhesion mediator activity | ISO PMID:8602532 CNS gene encoding astrotactin, which supports neuronal migra... | NEW | Summary: Cell-cell adhesion mediator activity (NEW, ISO from mouse Astn1). Expressing astrotactin in 3T3 cells confers binding to glia, a gain-of-function adhesion assay. Astn1-null granule cells bind glia less, and surface-exposed ASTN1 is described as the ligand for neuron-glia adhesion. The term needs no knowledge of the counter-receptor. GOA carries no MF row for ASTN1, and no MF is propagated to it by IBA. Reason: [PMID:8602532 "Transfection of astrotactin complementary DNA into 3T3 cells indicated that astrotactin acts as a ligand for neuron-glia binding during neuronal migration."] [PMID:11861479 "In vitro and in vivo cerebellar granule cell assays show a decrease in neuron-glial binding, a reduction in migration rates and abnormal development of Purkinje cells."] [PMID:20573900 "ASTN1 is exposed on the cell surface and, as demonstrated previously ( Stitt and Hatten, 1990 ; Zheng et al., 1996 ), provides a ligand for neuron-glial adhesion during migration."] Supporting Evidence: PMID:8602532 Transfection of astrotactin complementary DNA into 3T3 cells indicated that astrotactin acts as a ligand for neuron-glia binding during neuronal migration. PMID:11861479 In vitro and in vivo cerebellar granule cell assays show a decrease in neuron-glial binding, a reduction in migration rates and abnormal development of Purkinje cells. PMID:20573900 ASTN1 is exposed on the cell surface and, as demonstrated previously ( Stitt and Hatten, 1990 ; Zheng et al., 1996 ), provides a ligand for neuron-glial adhesion during migration. |
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Download this section (compressed HTML)Q: What is the glial counter-receptor for ASTN1, and does ASTN2 bind ASTN1 in cis to gate adhesion or only to direct its endocytosis?
Experiment: Use proximity labelling or an ASTN1 ectodomain-Fc probe on Bergmann glia to identify the glial receptor, then test binding-deficient ASTN1 mutants for rescue of granule-cell migration in Astn1-null slices.
What is not known — curated, literature-grounded statements of the open unknowns (the inverse of core functions).
Gap: The glial counter-receptor that ASTN1 binds, and the ASTN1 region that contacts it, are unknown.
OPEN BIOLOGY
What is known: Established: ASTN1 confers neuron-glia binding and is needed for normal migration rates (mouse antibody, transfection and knockout studies). It is a surface membrane protein whose level is controlled by ASTN2 and endocytosis. Not established: the glial binding partner, which ASTN1 domain contacts it, and whether ASTN1 also signals. The adhesion-mediator activity itself is annotated (GO:0098632); only its partner is unknown, so no GO aspect is labelled dark.
Provenance (the field's own admissions):
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