Vav3-Deficient Astrocytes Enhance the Dendritic Development of Hippocampal Neurons in an Indirect Co-culture System

Abstract

Vav proteins belong to the class of guanine nucleotide exchange factors (GEFs) that catalyze the exchange of guanosine diphosphate (GDP) by guanosine triphosphate (GTP) on their target proteins. Here, especially the members of the small GTPase family, Ras homolog family member A (RhoA), Ras-related C3 botulinum toxin substrate 1 (Rac1) and cell division control protein 42 homolog (Cdc42) can be brought into an activated state by the catalytic activity of Vav-GEFs. In the central nervous system (CNS) of rodents Vav3 shows the strongest expression pattern in comparison to Vav2 and Vav1, which is restricted to the hematopoietic system. Several studies revealed an important role of Vav3 for the elongation and branching of neurites. However, little is known about the function of Vav3 for other cell types of the CNS, like astrocytes. Therefore, the following study analyzed the effects of a Vav3 knockout on several astrocytic parameters as well as the influence of Vav3-deficient astrocytes on the dendritic development of cultured neurons. For this purpose, an indirect co-culture system of native hippocampal neurons and Vav3-deficient cortical astrocytes was used. Interestingly, neurons cultured in an indirect contact with Vav3-deficient astrocytes showed a significant increase in the dendritic complexity and length after 12 and 17 days in vitro (DIV). Furthermore, Vav3-deficient astrocytes showed an enhanced regeneration in the scratch wound heal assay as well as an altered profile of released cytokines with a complete lack of CXCL11, reduced levels of IL-6 and an increased release of CCL5. Based on these observations, we suppose that Vav3 plays an important role for the development of dendrites by regulating the expression and the release of neurotrophic factors and cytokines in astrocytes.

Unravelling cell type specific response to Parkinson’s Disease at single cell resolution

“…Re-clustering astrocytes separately revealed 6 distinguishable states astrocytes0 - astrocytes5 that were represented across all samples, see Figure 3 A-C . Pathway overrepresentation analysis showed that all the populations except for astrocytes3 show high expression of transcripts linked to synaptic functions ( LRRC4C 24 , VAV3 25 , CASK 26 ), ion (Solute Carrier family members SLC6A11, SLC39A12, SLC1A2 ) and calcium transport (Calmodulin CALM1 , Calcium Voltage-Gated Channel Auxiliary Subunit CACNB2 ), see Figure 3B, D, Tables 5-6 and Supplementary Figure 3 .…”

“…Astrocytes0 seems to be more resistant to PD: it is lost in PD in less significant numbers and has a high expression of markers linked to synapse growth and function SLC1A2 33 , LRRC4C 24 and VAV3 25 . Unlike astrocytes2, this population does not have transcripts related to the regulation of dopamine metabolism which may explain the resistance of these cells to PD pathology, see Figure 3B, D and Table 5-6 .…”

1-L Transcription in Alzheimer’s Disease

“…VAV3 (vav guanine nucleotide exchange factor 3) belongs to the GEFs (guanine nucleotide exchange factors) that catalyze the exchange of guanosine diphosphate (GDP) by guanosine triphosphate (GTP) on their target proteins, such as Ras homolog family member A (RhoA), Ras-related C3 botulinum toxin substrate 1(Rac1), and cell division control protein 42 homolog (Cdc42), ( Figure 4 ). Interestingly, VAV3-deficient astrocytes enhanced the dendritic development of hippocampal neurons [ 44 ].…”

The guanine nucleotide exchange factor Vav3 intervenes in the migration pathway of oligodendrocyte precursor cells on tenascin-C

“…In addition, previous studies have shown that Vav3 modulates OPC differentiation and supports remyelination in white matter lesions ( Ulc et al, 2019 ). Also, this GEF seems to limit dendritic development of hippocampal neurons, as demonstrated in an indirect co-culture system ( Wegrzyn et al, 2021 ).…”