The guanine nucleotide exchange factor Vav3 regulates differentiation of progenitor cells in the developing mouse retina

Abstract

The seven main cell types in the mammalian retina arise from multipotent retinal progenitor cells, a process that is tightly regulated by intrinsic and extrinsic signals. However, the molecular mechanisms that control proliferation, differentiation and cell-fate decisions of retinal progenitor cells are not fully understood yet. Here, we report that the guanine nucleotide exchange factor Vav3, a regulator of Rho-GTPases, is involved in retinal development. We demonstrate that Vav3 is expressed in the mouse retina during the embryonic period. In order to study the role of Vav3 in the developing retina, we generate Vav3-deficient mice. The loss of Vav3 results in an accelerated differentiation of retinal ganglion cells and cone photoreceptors during early and late embryonic development. We provide evidence that more retinal progenitor cells express the late progenitor marker Sox9 in Vav3-deficient mice than in wild-types. This premature differentiation is compensated during the postnatal period and late-born cell types such as bipolar cells and Müller glia display normal numbers. Taken together, our data imply that Vav3 is a regulator of retinal progenitor cell differentiation, thus highlighting a novel role for guanine nucleotide exchange factors in retinogenesis.

Involvement of the guanine nucleotide exchange factor Vav3 in central nervous system development and plasticity

“…TO-PRO-3 (blue) was used for nuclear counterstaining. The overproduction of different cell lineages has been previously reported (Luft et al, 2015). With ongoing postnatal development, the cellular lineage modification is compensated.…”

“…In the light of these observations, we carefully monitored the development of the distinct lineages of the retina in our Vav3 -/-model. We detected an overproduction of Tbr2-positive RGCs, Otx2-positive cone progenitors and an enhanced expression of the late progenitor marker Sox9 in the Vav3 -/-retina, while neither cell death nor proliferation rates were changed (Luft et al, 2015) (Figure 2). These modifications were compensated at later postnatal stages.…”

“…In order to study the functions of Vav3 in developing tissues, we initially characterized a novel Vav3 knockout mouse model in collaboration with the laboratories of K. D. Fischer (Magdeburg, Germany) and M. Shibuya (Tokyo, Japan) (Luft et al, 2015). Other laboratories had already shown that the ablation of Vav3 by homologous recombination results in a viable mouse line.…”

The guanine nucleotide exchange factor Vav3 modulates oligodendrocyte precursor differentiation and supports remyelination in white matter lesions

“…We have previously shown that the treatment of neurospheres with Tenascin C (TnC) led to a decreased expression of Vav3 (Moritz, Lehmann, Faissner, & von Holst, ), and that the cultivation of OPCs on TnC‐coated dishes resulted in impaired OPC differentiation and maturation (Czopka et al, ; Faissner & Reinhard, ; Faissner, Roll, & Theocharidis, ; Garwood et al, ). To investigate whether Vav3 was directly involved in differentiation, we studied OLs obtained from the recently described Vav3 −/− mouse (Luft et al, ). For this purpose, Vav3 +/+ and Vav3 −/− OPCs were isolated via immunopanning and cultivated for 2 days under differentiating conditions.…”

“…Here, we investigate the role of Vav3 during OL differentiation and myelination as well as remyelination studying the recently described Vav3 knockout mouse (Luft et al, ). We highlight that Vav3 deficient OLs show an enhanced differentiation, whereas their capacities for myelination and remyelination are impaired.…”