Functional Redundancy of Sos1 and Sos2 for Lymphopoiesis and Organismal Homeostasis and Survival

Abstract

dSos1 and Sos2 are ubiquitously expressed, universal Ras guanine nucleotide exchange factors (Ras-GEFs) acting in multiple signal transduction pathways activated by upstream cellular kinases. The embryonic lethality of Sos1 null mutants has hampered ascertaining the specific in vivo contributions of Sos1 and Sos2 to processes controlling adult organism survival or development of hematopoietic and nonhematopoietic organs, tissues, and cell lineages. Here, we generated a tamoxifen-inducible Sos1-null mouse strain allowing analysis of the combined disruption of Sos1 and Sos2 (Sos1/2) during adulthood. Sos1/2 double-knockout (DKO) animals died precipitously, whereas individual Sos1 and Sos2 knockout (KO) mice were perfectly viable. A reduced percentage of total bone marrow precursors occurred in single-KO animals, but a dramatic depletion of B-cell progenitors was specifically detected in Sos1/2 DKO mice. We also confirmed a dominant role of Sos1 over Sos2 in early thymocyte maturation, with almost complete thymus disappearance and dramatically higher reduction of absolute thymocyte counts in Sos1/2 DKO animals. Absolute counts of mature B and T cells in spleen and peripheral blood were unchanged in single-KO mutants, while significantly reduced in Sos1/2 DKO mice. Our data demonstrate functional redundancy between Sos1 and Sos2 for homeostasis and survival of the full organism and for development and maturation of T and B lymphocytes.

Frontline Science: TNF-α and GM-CSF1 priming augments the role of SOS1/2 in driving activation of Ras, PI3K-γ, and neutrophil proinflammatory responses

“…However, we could only recover approximately 2 × 10 6 neutrophils/mouse from these mice, about 20–25% of the yield from control mice indicating that SOS1/2 may have an important role in differentiation or proliferation of neutrophil progenitors. In fact, a previous report showed that other bone marrow progenitors such as lymphocyte progenitors were also affected by SOS1/2 depletion and that the peripherical neutrophils number was also down …”

“…The PLCβ2 –/– x PLCβ3 –/– mice (generously provided by D. Wu, Yale university, USA), the RasGRP4 –/– mice, the p110‐γ mice (generously provided by M. Wymann, Basel, Switzerland), and SOS1/2 DKO (SOS1 fl‐Cre/fl‐Cre /SOS 2 –/– and their control (SOS1 +‐Cre/+‐Cre /SOS 2 +/+ ) mice (generously provided by E. Santos, Salamanca, Spain) have been previously described. In the case of the latter mice, to obtain a complete deletion of SOS1, the mice were fed for 5 days on a soya‐free diet and then for 10 days on a tamoxifen‐containing chow diet (Harlan, Teklad TAM 400/creER).…”

Bone marrow transplantation improves motor activity in a mouse model of ataxia

“…This integration is especially important after muscular damage, given the anti‐inflammatory properties of the bone marrow‐derived cells (Fujita et al, ). Hence, it is plausible to consider that in PCD mice, this endogenous mechanism of muscle turnover may be impaired, because these animals may present abnormal patterns of inflammation, as it occurs in their central nervous system (Baltanás, Berciano, et al, ). Conversely, when wild‐type bone marrow cells substitute the bone marrow cells of the mutant animals, the process could take place properly and mediate normal turnover in the muscle.…”

Unique dependence on Sos1 in KrasG12D-induced leukemogenesis

“…Our result is consistent with a previous report that Sos1 is dispensable for mouse survival, and its function is likely to be compensated by other Ras guanine nucleotide exchange factors. 14 In contrast, in Kras cells, Sos1 deficiency abolished hyperactivation of WT Nras and Hras without a significant effect on total Kras-GTP or Kras G12D -GTP level ( Figure 1D). Associated with downregulation of WT Nras and Hras activation, GM-CSFstimulated ERK and STAT5 activation were also greatly reduced in Kras;Sos1 2/2 cells compared with Kras cells ( Figure 1E).…”