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Vav3-deficient mice exhibit a transient delay in cerebellar development.

Quevedo C, Sauzeau V, Menacho-Márquez M, Castro-Castro A, Bustelo XR - Mol. Biol. Cell (2010)

Bottom Line: We report here that Vav3 is expressed at high levels in Purkinje and granule cells, suggesting additional roles for this protein in the cerebellum.Using primary neuronal cultures, we show that Vav3 is important for dendrite branching, but not for primary dendritogenesis, in Purkinje and granule cells.These results indicate that Vav3 function contributes to the timely developmental progression of the cerebellum.

View Article: PubMed Central - PubMed

Affiliation: Centro de Investigación del Cáncer and Instituto de Biología Molecular y Celular del Cáncer, Consejo Superior de Investigaciones Científicas, University of Salamanca, Campus Unamuno, E-37007 Salamanca, Spain.

ABSTRACT
Vav3 is a guanosine diphosphate/guanosine triphosphate exchange factor for Rho/Rac GTPases that has been involved in functions related to the hematopoietic system, bone formation, cardiovascular regulation, angiogenesis, and axon guidance. We report here that Vav3 is expressed at high levels in Purkinje and granule cells, suggesting additional roles for this protein in the cerebellum. Consistent with this hypothesis, we demonstrate using Vav3-deficient mice that this protein contributes to Purkinje cell dendritogenesis, the survival of granule cells of the internal granular layer, the timely migration of granule cells of the external granular layer, and to the formation of the cerebellar intercrural fissure. With the exception of the latter defect, the dysfunctions found in Vav3(-/-) mice only occur at well-defined postnatal developmental stages and disappear, or become ameliorated, in older animals. Vav2-deficient mice do not show any of those defects. Using primary neuronal cultures, we show that Vav3 is important for dendrite branching, but not for primary dendritogenesis, in Purkinje and granule cells. Vav3 function in the cerebellum is functionally relevant, because Vav3(-/-) mice show marked motor coordination and gaiting deficiencies in the postnatal period. These results indicate that Vav3 function contributes to the timely developmental progression of the cerebellum.

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Histological and cytological alterations in cerebella obtained from Vav3-deficient mice. (A) Sagittal cerebellar sections from P15 (top) and adult stages (bottom) obtained from wild-type (left) and Vav3-deficient (right) were stained with hematoxylin and eosin and analyzed by light microscopy. Bar, 1 mm. It is observed a normal structure of the cerebella of Vav3-deficient mice, with the exception of a poorly developed intercrural fissure that separates cerebellar lobules VI and VII (compare areas of the left and right panels that have been pointed out by arrows). (B) Detection by immunofluorescence of the expression of GFAP in sagittal cerebellar sections obtained from P6 wild-type (left) and Vav3−/− (right) mice. Pictures show representative images obtained in cerebellar lobule IV. Similar results were obtained in the rest of cerebellar lobules analyzed (data not shown). Bar, 60 μm. No changes in the distribution of GFAP are seen in the cerebella of control and Vav3-deficient mice.
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Figure 2: Histological and cytological alterations in cerebella obtained from Vav3-deficient mice. (A) Sagittal cerebellar sections from P15 (top) and adult stages (bottom) obtained from wild-type (left) and Vav3-deficient (right) were stained with hematoxylin and eosin and analyzed by light microscopy. Bar, 1 mm. It is observed a normal structure of the cerebella of Vav3-deficient mice, with the exception of a poorly developed intercrural fissure that separates cerebellar lobules VI and VII (compare areas of the left and right panels that have been pointed out by arrows). (B) Detection by immunofluorescence of the expression of GFAP in sagittal cerebellar sections obtained from P6 wild-type (left) and Vav3−/− (right) mice. Pictures show representative images obtained in cerebellar lobule IV. Similar results were obtained in the rest of cerebellar lobules analyzed (data not shown). Bar, 60 μm. No changes in the distribution of GFAP are seen in the cerebella of control and Vav3-deficient mice.

Mentions: The expression of Vav3 in cerebellum led us to investigate whether the Vav3 deficiency could induce defects in the development, structure, or functional status of this organ. Histological analysis indicated that the size of the cerebella of Vav3-deficient mice was similar to that observed in wild-type controls. Moreover, the Vav3 deficiency did not induce any major defect in the overall cerebellar structure, both at P15 (Figure 2A, top) and in the adult period (Figure 2A, bottom). Consistent with this, we observed a fully mature foliation pattern within the vermis of Vav3-deficient cerebella, including the detection of the characteristic folia that were separated by well-developed fissures (Figure 2A). The only exception was the absence of the intercrural fissure, the invagination of the cerebellum that separates lobule VI from lobule VII. This deficiency was consistently observed in both P15 and adult Vav3-deficient mice (Figure 2A, right, arrows). The overall cytoarchitectural organization of the Vav3-deficient cerebella also seemed wild type-like, as assessed by the identification of well-defined molecular, Purkinje, and granular cell layers (Figure 2A). The distribution and morphology of radial glia cells was also normal, as demonstrated by immunofluorescence experiments with antibodies to GFAP (Figure 2B). Altogether, these results indicate that the Vav3 deficiency does not induce major defects in folia development, laminar structure, or glial scaffold organization. Instead, Vav3 participates in the formation of the intercrural fissure.


Vav3-deficient mice exhibit a transient delay in cerebellar development.

Quevedo C, Sauzeau V, Menacho-Márquez M, Castro-Castro A, Bustelo XR - Mol. Biol. Cell (2010)

Histological and cytological alterations in cerebella obtained from Vav3-deficient mice. (A) Sagittal cerebellar sections from P15 (top) and adult stages (bottom) obtained from wild-type (left) and Vav3-deficient (right) were stained with hematoxylin and eosin and analyzed by light microscopy. Bar, 1 mm. It is observed a normal structure of the cerebella of Vav3-deficient mice, with the exception of a poorly developed intercrural fissure that separates cerebellar lobules VI and VII (compare areas of the left and right panels that have been pointed out by arrows). (B) Detection by immunofluorescence of the expression of GFAP in sagittal cerebellar sections obtained from P6 wild-type (left) and Vav3−/− (right) mice. Pictures show representative images obtained in cerebellar lobule IV. Similar results were obtained in the rest of cerebellar lobules analyzed (data not shown). Bar, 60 μm. No changes in the distribution of GFAP are seen in the cerebella of control and Vav3-deficient mice.
© Copyright Policy
Related In: Results  -  Collection

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getmorefigures.php?uid=PMC2836963&req=5

Figure 2: Histological and cytological alterations in cerebella obtained from Vav3-deficient mice. (A) Sagittal cerebellar sections from P15 (top) and adult stages (bottom) obtained from wild-type (left) and Vav3-deficient (right) were stained with hematoxylin and eosin and analyzed by light microscopy. Bar, 1 mm. It is observed a normal structure of the cerebella of Vav3-deficient mice, with the exception of a poorly developed intercrural fissure that separates cerebellar lobules VI and VII (compare areas of the left and right panels that have been pointed out by arrows). (B) Detection by immunofluorescence of the expression of GFAP in sagittal cerebellar sections obtained from P6 wild-type (left) and Vav3−/− (right) mice. Pictures show representative images obtained in cerebellar lobule IV. Similar results were obtained in the rest of cerebellar lobules analyzed (data not shown). Bar, 60 μm. No changes in the distribution of GFAP are seen in the cerebella of control and Vav3-deficient mice.
Mentions: The expression of Vav3 in cerebellum led us to investigate whether the Vav3 deficiency could induce defects in the development, structure, or functional status of this organ. Histological analysis indicated that the size of the cerebella of Vav3-deficient mice was similar to that observed in wild-type controls. Moreover, the Vav3 deficiency did not induce any major defect in the overall cerebellar structure, both at P15 (Figure 2A, top) and in the adult period (Figure 2A, bottom). Consistent with this, we observed a fully mature foliation pattern within the vermis of Vav3-deficient cerebella, including the detection of the characteristic folia that were separated by well-developed fissures (Figure 2A). The only exception was the absence of the intercrural fissure, the invagination of the cerebellum that separates lobule VI from lobule VII. This deficiency was consistently observed in both P15 and adult Vav3-deficient mice (Figure 2A, right, arrows). The overall cytoarchitectural organization of the Vav3-deficient cerebella also seemed wild type-like, as assessed by the identification of well-defined molecular, Purkinje, and granular cell layers (Figure 2A). The distribution and morphology of radial glia cells was also normal, as demonstrated by immunofluorescence experiments with antibodies to GFAP (Figure 2B). Altogether, these results indicate that the Vav3 deficiency does not induce major defects in folia development, laminar structure, or glial scaffold organization. Instead, Vav3 participates in the formation of the intercrural fissure.

Bottom Line: We report here that Vav3 is expressed at high levels in Purkinje and granule cells, suggesting additional roles for this protein in the cerebellum.Using primary neuronal cultures, we show that Vav3 is important for dendrite branching, but not for primary dendritogenesis, in Purkinje and granule cells.These results indicate that Vav3 function contributes to the timely developmental progression of the cerebellum.

View Article: PubMed Central - PubMed

Affiliation: Centro de Investigación del Cáncer and Instituto de Biología Molecular y Celular del Cáncer, Consejo Superior de Investigaciones Científicas, University of Salamanca, Campus Unamuno, E-37007 Salamanca, Spain.

ABSTRACT
Vav3 is a guanosine diphosphate/guanosine triphosphate exchange factor for Rho/Rac GTPases that has been involved in functions related to the hematopoietic system, bone formation, cardiovascular regulation, angiogenesis, and axon guidance. We report here that Vav3 is expressed at high levels in Purkinje and granule cells, suggesting additional roles for this protein in the cerebellum. Consistent with this hypothesis, we demonstrate using Vav3-deficient mice that this protein contributes to Purkinje cell dendritogenesis, the survival of granule cells of the internal granular layer, the timely migration of granule cells of the external granular layer, and to the formation of the cerebellar intercrural fissure. With the exception of the latter defect, the dysfunctions found in Vav3(-/-) mice only occur at well-defined postnatal developmental stages and disappear, or become ameliorated, in older animals. Vav2-deficient mice do not show any of those defects. Using primary neuronal cultures, we show that Vav3 is important for dendrite branching, but not for primary dendritogenesis, in Purkinje and granule cells. Vav3 function in the cerebellum is functionally relevant, because Vav3(-/-) mice show marked motor coordination and gaiting deficiencies in the postnatal period. These results indicate that Vav3 function contributes to the timely developmental progression of the cerebellum.

Show MeSH
Related in: MedlinePlus