InteractiveFly: GeneBrief

Discoidin domain receptor: Biological Overview | References

Most invertebrate axons and small caliber axons in mammalian peripheral nerves are unmyelinated but still ensheathed by glia. This study used Drosophila wrapping glia to study the development and function of non-myelinating axon ensheathment, which is poorly understood. Selective ablation of these glia from peripheral nerves severely impaired larval locomotor behavior. In an in vivo RNAi screen to identify glial genes required for axon ensheathment, the conserved receptor tyrosine kinase Discoidin domain receptor (Ddr) was identified. In larval peripheral nerves, loss of Ddr resulted in severely reduced ensheathment of axons and reduced axon caliber, and a strong dominant genetic interaction was found between Ddr and the type XV/XVIII collagen Multiplexin (Mp), suggesting Ddr functions as a collagen receptor to drive axon wrapping. In adult nerves, loss of Ddr decreased long-term survival of sensory neurons and significantly reduced axon caliber without overtly affecting ensheathment. These data establish essential roles for non-myelinating glia in nerve development, maintenance, and function, and identify Ddr as a key regulator of axon-glia interactions during ensheathment and establishment of axon caliber (Corty, 2022).

Non-myelinating ensheathment of axons is a conserved but understudied feature of the PNS. Although this type of multi-axonal ensheathment has been less studied compared with myelination, a growing body of evidence indicates it is important for the health and function of neurons and axons in the periphery. For example, Schwann cell-specific loss of the transmembrane receptor LDL receptor related protein-1 (LRP1) causes both thin myelin and abnormal Remak bundle structure. These conditional knockout animals also showed a lowered pain threshold, suggesting that the physiology of nociceptor neurons is impaired when Remak ensheathment is disrupted. Disrupting metabolism in Schwann cells causes progressive axon loss, with small unmyelinated fibers dying first, before myelinated fibers begin to show signs of degeneration. In the fly, disruption of axonal wrapping leads to uncoordinated behavioral responses that hint at aberrant ephaptic coupling between neighboring axons in nerves when not properly separated (Kottmeier, 2020). Such coupling could cause the inappropriate activation of sensory or nociceptive neurons underlying peripheral neuropathies. Previous studies lab have shown that wrapping glia are required to clear neuronal debris after nerve injury and mediate injury signaling between injured and intact 'bystander' neurons, which might be important for functional recovery after nerve trauma. These and other findings suggest that Remak-type ensheathment and axon-glia signaling of unmyelinated fibers play a variety of underappreciated roles in peripheral nerve physiology that contribute to the pathophysiology of a number of PNS disorders, including debilitating peripheral neuropathies and responses to nerve injury (Corty, 2022).

To gain insight into non-myelinating ensheathment, the Drosophila peripheral nerves were used to identify a molecular pathway important for the development and function multi-axonal ensheathment. A new Split-Gal4 intersectional driver was generated to target wrapping glia more specifically for functional and behavioral studies in order to improve understanding of whether and how wrapping glia support axon health, physiology and, ultimately, circuit function. Finally, this study uncovered roles for glia in mediating long-term neuronal survival and driving increased axon caliber that are separable from overt effects on wrapping, demonstrating that non-myelinating ensheathing glia perform crucial, previously unappreciated, roles in nervous system development, maintenance and function (Corty, 2022).

A main advantage of Drosophila is the ability to conduct large-scale in vivo screens. Use was made of available UAS-RNAi libraries to carry out a broad screen for regulators of axonal ensheathment in intact nerves. This morphological screen was sensitive enough to identify genes previously implicated in wrapping glia development, including vn, LanB1 and mys, validating the approach. Moreover, in the case of Ddr, it was possible to identify an important regulator of ensheathment that a simple behavioral or lethality screen would have missed in light of follow-up behavioral testing. Knockdown of Ddr in wrapping glia resulted in reduced glial membrane coverage in nerve cross-sections by fluorescence microscopy. Similar phenotypes were observed in Ddr loss-of-function animals and could be rescued by resupplying Ddr specifically in wrapping glia, confirming the specificity of the RNAi results. TEM clearly showed that reduced glial membrane coverage at the light level corresponds to decreased axon wrapping (Corty, 2022).

Although neither of the vertebrate homologs, Ddr1 and Ddr2, has been explicitly implicated in glial development, several lines of evidence suggests that Ddr1 may have a conserved role in vertebrate glial development or function. Ddr1 is highly expressed in the mouse oligodendrocyte lineage starting from when the cells begin to associate with axons, is upregulated in newly formed oligodendrocytes after cuprizone treatment, and is expressed in both myelinating and Remak Schwann cells. Moreover, DDR1 is expressed in human oligodendrocytes and myelin, and variants in the human gene have been correlated with abnormal white matter and schizophrenia (Corty, 2022).

Vertebrate Ddr1 and Ddr2 are potently activated by collagens in vitro, prompting an investigation of whether collagens were involved with Ddr function in fly nerves. Knockdown of the Drosophila collagen Mp specifically in wrapping glia but not in neurons was found to disrupted ensheathment. Together with the established roles for vertebrate Ddr1 and Ddr2 as collagen receptors, the strong genetic interaction observed between Ddr and Mp is consistent with a model in which Mp acts as a collagen ligand for Ddr during axonal ensheathment. Although the Mp-GFP protein trap shows diffuse Mp expression throughout the nerve, it remains unclear precisely which cell type(s) within the nerve are producing it. Previous reports indicate that Mp can be expressed in the outer peripheral glia layers, so they may provide some Mp to the wrapping glia. However, the strong ensheathment defect seen when Mp is knocked down exclusively in wrapping glia indicates that wrapping glia themselves are likely to be the primary, relevant source of the Mp required for their own morphogenesis. Schwann cells similarly rely on components of their own basal lamina to regulate their development. For example, laminin-211 serves as a ligand for GPR126 to promote myelination. Mp is the sole Drosophila homolog of collagen types XV/XVIII, containing a central helical collagen region with a cleavable N-terminal thrombospondin-like domain and C-terminal endostatin-like domain. Collagen 15a1 and 18a1 are expressed in mouse peripheral nerves and Col15a1 mutants have radial-sorting defects, suggesting that the role of Mp in promoting axon wrapping is likely conserved. In fact, Mp appears to play multiple roles in nerve biology. For example, Mp secreted by the outer glia layers acts via its cleaved endostatin domain to modulate homeostatic plasticity at motor neuron synapses. How Ddr activation within wrapping glia ultimately drives axon wrapping still remains to be determined, but Ddr joins two other receptor tyrosine kinases - EGFR and FGFR - as important and conserved regulators of axon ensheathment. As a non-canonical collagen receptor, Ddr may also interact with other collagen receptors, such as integrins (known to play roles in wrapping glia development), to sense and remodel the extracellular matrix and permit extension of glia processes between axons, similar to its roles in promoting tumor metastasis (Corty, 2022).

The nrv2-Gal4 driver has been the standard method to genetically target wrapping glia for morphological studies, but it is imperfect for manipulation of wrapping glia in ablation or behavioral assays owing to its expression in several subtypes of CNS glia. This study generated a new Split-Gal4 intersectional driver that drives exclusively in wrapping glia. This allowed performing of precise ablation of wrapping glia that led to severely impaired larval locomotion, indicating that the wrapping glia are essential for basic crawling circuit function. This phenotype was particularly striking in light of that fact that no clear crawling defect was observed in Ddr mutant larvae, even though wrapping was severely impaired. It may be possible that non-contact-mediated mechanisms, such as one or more secreted factors, constitute the essential contribution of wrapping glia to axon health and physiology. Alternatively, perhaps even a small amount of direct glia-axon contact may be sufficient to support neuron health and axon function. This would be consistent with the lack of overt behavioral defects in newly hatched first instar larvae, which have poor wrapping compared with later stages, and even in wild-type third instar larvae, in which not every axon is individually wrapped. It is also consistent with our findings that many nerves in WG-ablated larvae seem to be missing axons, whereas this was not observed in Ddr mutant nerves. These results are also similar to what has been recently reported using a different approach to ablate wrapping glia, where only minor behavioral defects were observed upon FGFR signaling disruption but profound crawling defects were seen upon ablation. As with all ablation studies, it is not possible to strictly rule out unexpected negative side effects of the ablation itself; however, using a genetic approach should limit collateral damage (compared with laser or toxin approaches). Together, these data support the conclusion that even limited wrapping or simply some degree of glia-axon contact is sufficient to support axon survival and nerve function compared with no glia at all at least for the first ~5 days of larval life (Corty, 2022).

Previous studies of oligodendrocytes and Schwann cells have found that impairing glial function can result in seemingly normal wrapping and circuit function in young animals, with deficits only appearing when the system is stressed or aged. Studying wrapping in adult Drosophila allows for aging and maintenance studies that the short larval period precludes. Adult peripheral nerves are encased in a transparent but hard cuticle that allows for live imaging but makes fixation challenging. Because of the resolution limits of light microscopy, a reliable method was developed to study their ultrastructure using TEM. Ensheathment in the adult wing nerve was found to differ from that of the larva, as all axons appear to be separated by glial membranes. Surprisingly, wrapping was not obviously impaired in adult nerves of Ddr knockdown or mutant animals. One difference between larval and adult wrapping glia is the territory size of each cell. In larvae, one wrapping glia cell covers the majority of the nerve from the VNC to the muscle field. This wrapping glial cell must therefore undergo tremendous growth to keep up with nerve elongation as the animal grows, as well as radial growth to ensheathe axons. A single cell can end up covering from ~750 μm to 2.5 mm of nerve length, depending on the segment, whereas in the wing there are ~13 wrapping glia along the region of the L1 nerve that was analyzed; This is is ~400 μm long. In larval wrapping glia, there are three receptor tyrosine kinases (EGFR, the FGFR Heartless, and now Ddr) that are each required for normal ensheathment, and thus cannot fully compensate for one another. It is hypothesized that in the larva the cell is pushed to its growth limits and any perturbation in pro-wrapping signaling has a strong effect on morphology, whereas in the adult nerve the system is robust and redundant enough to withstand perturbations of single genes. Future studies of double and triple mutants may be able to test this hypothesis (Corty, 2022).

Loss of Ddr led to an increase in spontaneous neurodegeneration in the nerve as animals naturally aged. Such an uncoupling of neuron health from overt effects on myelination has been demonstrated previously. For example, Cnp1 (Cnp) mutant mice show severe age-dependent neurodegeneration, although they have grossly normal myelin with only subtle changes in myelin ultrastructure. Loss of the proteolipid PLP results in axon degeneration despite having largely normal myelin. It was found that the number of VGlut+ neurons was reduced in aged wings of Ddr knockdown animals, indicating that wrapping glial Ddr is important for long-term neuronal survival. When Ddr whole animal mutants were analyzed by TEM a small but significant reduction was found in axon profile number, which should correspond to the number of surviving neurons. Together with the increased variability observed, this suggests that absence of Ddr signaling increases the susceptibility of subpopulations of neurons to insult or injury that may underlie age-related degeneration (Corty, 2022).

Myelination can directly affect the structure and function of the axons they wrap, including controlling caliber. In general, myelination increases caliber. For example, dysmyelinated Trembler mice have reduced axon calibers compared with controls, and in the PNS caliber along a single axon can vary with reduced caliber at points without direct myelin contact, such as nodes of Ranvier. Axon caliber is an important determinant of conduction velocity but varies widely between neuronal subtypes, so achieving and maintaining appropriate caliber is crucial for proper circuit function. How non-myelinating ensheathment impacts axon caliber is not understood. This study found glial Ddr promotes increased axon caliber. This study focused on the distal twin sensilla of the margin (dTSM) neuron, so it was possible to directly compare the caliber of an identifiable axon between conditions. The reductions in caliber were similar between Ddr mutants and glial-specific DdrRNAi, supporting a non-cell-autonomous role for glial Ddr in regulating axon caliber. The effect is considerable: nearly a 50% reduction in axon caliber at 5 dpe. We hypothesize that by this time point, wild-type dTSM axons have reached their mature caliber, as it is comparable between 5 dpe and 28 dpe in comparable genetic backgrounds. In Ddr mutants, however, we observe that the relative size compared with controls changes over time, suggesting that in Ddr mutants (or knockdowns) the axon continues to increase its caliber, perhaps in an effort to achieve the optimal size, although the axons still remain ~25% smaller than wild-type axons at 28 dpe (Corty, 2022).

Two proteins, MAG, which acts to increase the caliber of myelinated axons, and CMTM6, which restricts the caliber of myelinated and unmyelinated axons, are the only proteins reported to non-cell-autonomously affect the caliber of vertebrate axons, and both do so without overtly affecting myelin. In the fly, it has been shown that a shift in the average size of axons in larval nerves when wrapping glia are absent or severely disrupted, supporting a general role for wrapping glia in promoting axon size. In the adult, this study showed that Ddr is still required for increased axon caliber even when wrapping appears intact. The exact molecular mechanism by which Ddr may promote increased caliber size remains unclear as the control of axon caliber, generally, is not well understood. Genes involved in the general regulation of cell size have been implicated as cell-autonomous determinants. For example, in the fly, S6 kinase signaling is a positive regulator of motor neuron size, including axon caliber. In mammalian axons, the phosphorylation state of neurofilaments and microtubules determines their spacing to determine caliber. Determining how glial Ddr activity ultimately influences the axonal cytoskeleton is an important next step. A 25-50% reduction in caliber would be predicted to impact conduction velocity along the dTSM axon. Given that campaniform sensilla provide essential rapid sensory feedback to fine-tune movement, it will be of interest to test conduction velocity and flight behavior in Ddr mutant animals to see how the proprioceptive circuit might be affected (Corty, 2022).

Taken together, these studies identify Ddr as an important regulator of wrapping glia development and function in the fly, with distinct roles in larval and adult wrapping glia. Ddr is essential for the normal morphological development of axon wrapping in the larvae, and also mediates important axon-glia communication that controls axon caliber growth and affects neuronal health and survival. Given its expression pattern in vertebrate oligodendrocytes and Schwann cells, it seems likely that these essential functions are conserved in vertebrates. Further study into how Ddr functions in both fly and vertebrate glia promises to increase understanding of axon ensheathment in health and disease (Corty, 2022).

Evidence That DDR1 Promotes Oligodendrocyte Differentiation during Development and Myelin Repair after Injury

Oligodendrocytes generate myelin sheaths vital for the formation, health, and function of the central nervous system. Mounting evidence suggests that receptor tyrosine kinases (RTKs) are crucial for oligodendrocyte differentiation and myelination in the CNS. It was recently reported that discoidin domain receptor 1 (Ddr1), a collagen-activated RTK, is expressed in oligodendrocyte lineage. However, its specific expression stage and functional role in oligodendrocyte development in the CNS remain to be determined. This study reports that Ddr1 is selectively upregulated in newly differentiated oligodendrocytes in the early postnatal CNS and regulates oligodendrocyte differentiation and myelination. Ddr1 knock-out mice of both sexes displayed compromised axonal myelination and apparent motor dysfunction. Ddr1 deficiency alerted the ERK pathway, but not the AKT pathway in the CNS. In addition, Ddr1 function is important for myelin repair after lysolecithin-induced demyelination. Taken together, the current study described the role of Ddr1 in myelin development and repair in the CNS, providing a novel molecule target for the treatment of demyelinating diseases (Mei, 2023).

DDR1 and Its Ligand, Collagen IV, Are Involved in In Vitro Oligodendrocyte Maturation

Discoidin domain receptor 1 (DDR1) is a tyrosine kinase receptor expressed in epithelial cells from different tissues in which collagen binding activates pleiotropic functions. In the brain, DDR1 is mainly expressed in oligodendrocytes (OLs), the function of which is unclear. Whether collagen can activate DDR1 in OLs has not been studied. This study assessed the expression of DDR1 during in vitro OL differentiation, including collagen IV incubation, and the capability of collagen IV to induce DDR1 phosphorylation. Experiments were performed using two in vitro models of OL differentiation: OLs derived from adult rat neural stem cells (NSCs) and the HOG16 human oligodendroglial cell line. Immunocytofluorescence, western blotting, and ELISA were performed to analyze these questions. The differentiation of OLs from NSCs was addressed using oligodendrocyte transcription factor 2 (Olig2) and myelin basic protein (MBP). In HOG16 OLs, collagen IV induced DDR1 phosphorylation through slow and sustained kinetics. In NSC-derived OLs, DDR1 was found in a high proportion of differentiating cells (MBP+/Olig2+), but its protein expression was decreased in later stages. The addition of collagen IV did not change the number of DDR1+/MBP+ cells but did accelerate OL branching. This study provides the first demonstration that collagen IV mediates the phosphorylation of DDR1 in HOG16 cells and that the in vitro co-expression of DDR1 and MBP is associated with accelerated branching during the differentiation of primary OLs (Silva, 2023).

Coexpression of the discoidin domain receptor 1 gene with oligodendrocyte-related and schizophrenia risk genes in the developing and adult human brain

Discoidin domain receptor tyrosine kinase 1 (DDR1) is present in multiple types of epithelial cells and is highly expressed in the nervous system. Previous studies have revealed that DDR1 is involved in schizophrenia (SCZ). Although the expression of DDR1 in oligodendrocytes has been described, its role in brain myelination is not well understood. This study aimed to explore the coexpression network of DDR1 in the human brain and to compare the list of DDR1 coexpressing genes with the list of genes containing single nucleotide polymorphisms (SNPs) that are associated with SCZ. A weighted gene coexpression network analysis (WGCNA) of a dataset from four brain areas (the dorsolateral prefrontal cortex, primary motor cortex, hippocampus, and striatum) and from four different intervals (I) of life (I-1 = 10-38 weeks postconception, I-2 >/=0 to < 6 years, I-3 >/= 6 to < 40 years, and I-4 >p/= 40 years of age). The list of genes that are associated with SCZ in the GWAS Catalog was comparedwith the list of genes coexpressing with DDR1 in each interval. This study revealed that DDR1 was coexpressed with oligodendrocyte-related genes mainly in I-2 and I-3, which coincided with the coexpression of DDR1 with myelination-related genes. DDR1 was also coexpressed with astrocyte-related genes in I-1, I-2 and I-4 and with type 2 microglia-related genes in I-1, I-2 and I-4. Moreover, significant enrichment of SCZ susceptibility genes was onserved within the coexpression modules containing DDR1 in I-1 and I-4, during which the DDR1 module showed the highest association with the astrocytes. Yhid study confirmed that DDR1 is coexpressed with oligodendrocyte- and myelin-related genes in the human brain but suggests that DDR1 may contribute mainly to SCZ risk through its role in other glial cell types, such as astrocytes (Muntane, 2021).

Collective cell migration requires suppression of actomyosin at cell-cell contacts mediated by DDR1 and the cell polarity regulators Par3 and Par6

Collective cell migration occurs in a range of contexts: cancer cells frequently invade in cohorts while retaining cell-cell junctions. This study shows that collective invasion by cancer cells depends on decreasing actomyosin contractility at sites of cell-cell contact. When actomyosin is not downregulated at cell-cell contacts, migrating cells lose cohesion. A molecular mechanism is provided for this downregulation. Depletion of discoidin domain receptor 1 (DDR1) blocks collective cancer-cell invasion in a range of two-dimensional, three-dimensional and 'organotypic' models. DDR1 coordinates the Par3/Par6 cell-polarity complex through its carboxy terminus, binding PDZ domains in Par3 and Par6. The DDR1-Par3/Par6 complex controls the localization of RhoE to cell-cell contacts, where it antagonizes ROCK-driven actomyosin contractility. Depletion of DDR1, Par3, Par6 or RhoE leads to increased actomyosin contactility at cell-cell contacts, a loss of cell-cell cohesion and defective collective cell invasion (Hidalgo-Carcedo, 2011).

Collective movement requires the coordination of actomyosin organization between cells. Actomyosin contractility is high around the edge of the cell cluster and low between cells. At the margin of the group, actomyosin is organized in a supracellular structure analogous to the 'purse-string' observed in epithelial wound closure. Both the elevated actomyosin levels observed around the edges of groups of invading cancer cells and 'purse-string' wound closure are dependent on Cdc42. Force is transmitted between cells through cell-cell contacts near the edge of the group. However, if force is applied uniformly around the cell margin, the cell junctions become compromised and the coordination of movement between neighbouring cells fails. Consistent with this, contact inhibition of locomotion and cell-cell repulsion are associated with increased Rho-driven actomyosin contraction function after cell-cell contact. Therefore a mechanism is required to decrease actomyosin contractility at sites of cell-cell contact. DDR1 acts in a new non-collagen-binding capacity at cell-cell contacts. The localization of DDR1 to cell-cell contacts requires E-cadherin. Once localized at cell-cell contacts, DDR1 helps to recruit Par3 and Par6; these molecules are required for efficient collective invasion. Cell polarity regulators are required for optimal migration in two-dimensional scratch/wound assays, which have some aspects of a collective nature. Moreover, Par3 and Par6 are required for collective migration of border cells in the Drosophila embryo41. The DDR1-Par3/Par6 complex then controls the localization of RhoE. RhoE may be localized through the intermediary p190ARhoGAP, which can bind both Par6 and RhoE. Consistent with this, depletion of p190ARhoGAP gave a similar phenotype to that after DDR1 or Par3/Par6 depletion. Both RhoE and p190ARhoGAP can antagonize Rho-ROCK-mediated regulation of actomyosin. The Par3-dependent suppression of actomyosin that was observe reciprocates the suppression of Par3 function by the actomyosin regulator ROCK. It is likely that the reciprocal nature of these negative interactions serves to segregate Par3 and actomyosin robustly. The DDR1-dependent mechanism that is describe most probably acts together with other proteins to decrease Rho-ROCK function at cell-cell contacts, such as p120 catenin-dependent mechanisms. This analysis has not yet allowed determination of all the components of DDR1 complexes at cell-cell contacts (Hidalgo-Carcedo, 2011).

Various regulators of cell polarity become misregulated in cancer; this has been linked to increased metastasis. It is believed that disruption of DDR1-dependent Par3 localization to cell-cell contacts might be expected to favour blood-borne metastasis. The data do not exclude a positive role for DDR1 in metastasis as a collagen receptor. Indeed, it was found that interference with DDR1 function in metastatic MTLn3 cells decreased their ability to colonize lung tissue. DDR1 expression may therefore not correlate simply with metastatic ability, but it is important to consider whether it is acting in a cell-matrix or cell-cell adhesion context: in the former it may promote single-cell cancer invasion and processes such as lung colonization; in the latter it may only promote more local and lymphatic invasion and hinder haematogenous metastasis. It is likely that DDR1 engages in different molecular complexes depending on whether it is involved in cell-cell interactions or cell-matrix interactions. For example, the data suggest that DDR1 does not associate with myosin IIa at cell-cell contacts but it has been reported to associate with myosin IIa in other contexts (Hidalgo-Carcedo, 2011).

This study described a mechanism that is required to decrease actomyosin contractility at sites of cell-cell contact. DDR1 acts in a new non-collagen-binding capacity at cell-cell contacts. DDR1 helps to recruit Par3 and Par6; this complex then controls the localization of RhoE, which can antagonize Rho-ROCK-mediated regulation of actomyosin. Thus, DDR1 functions at cell-cell contacts to keep actomyosin activity at low levels. Without this decrease in actomyosin activity, cell cohesion cannot be maintained during collective cell migration (Hidalgo-Carcedo, 2011).

Search PubMed for articles about Drosophila Ddr

Corty, M. M., Hulegaard, A. L., Hill, J. Q., Sheehan, A. E., Aicher, S. A. and Freeman, M. R. (2022). Discoidin domain receptor regulates ensheathment, survival, and caliber of peripheral axons. Development. PubMed ID: 36355066

Hidalgo-Carcedo, C., et al. (2011). Collective cell migration requires suppression of actomyosin at cell-cell contacts mediated by DDR1 and the cell polarity regulators Par3 and Par6. Nat. Cell Biol. 13(1): 49-58. PubMed Citation: 21170030

Kottmeier, R., Bittern, J., Schoofs, A., Scheiwe, F., Matzat, T., Pankratz, M. and Klambt, C. (2020). Wrapping glia regulates neuronal signaling speed and precision in the peripheral nervous system of Drosophila. Nat Commun 11(1): 4491. PubMed ID: 32901033

Mei. R., Qiu, W., Yang, Y., Xu, S., Rao, Y., Li, Q., Luo, Y., Huang, H., Yang, A., Tao, H., Qiu, M., Zhao, X. (2023). Evidence That DDR1 Promotes Oligodendrocyte Differentiation during Development and Myelin Repair after Injury. Int J Mol Sci24(12). PubMed ID: 37373466

Muntane, G., Chillida, M., Aranda, S., Navarro, A., Vilella, E. (2021). Coexpression of the discoidin domain receptor 1 gene with oligodendrocyte-related and schizophrenia risk genes in the developing and adult human brain. Brain Behav11(8):e2309. PubMed ID: 34323026

Silva, M. E., Hernandez-Andrade, M., Abasolo, N., Espinoza-Cruells, C., Mansilla, J. B., Reyes, C. R., Aranda, S., Esteban, Y., Rodriguez-Calvo, R., Martorell, L., Muntane, G., Rivera, F. J., Vilella, E. (2023). DDR1 and Its Ligand, Collagen IV, Are Involved in In Vitro Oligodendrocyte Maturation. Int J Mol Sci24(2). PubMed ID: 36675255

date revised: 20 December 2023

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