In BRGSKWv Wv mice the level of

In BRGSKWv/Wv mice, the level of myeloid reconstitution was up to 30% and 60% at 8–12 weeks and 20–24 weeks after transplantation, respectively. These levels might be comparable with those in MITRG mice in which four critical myeloid cytokines were humanized (Rongvaux et al., 2014), although a direct comparison is difficult owing to differences in dose, source, and injection methods of human HSPCs. Specifically, MITRG mice were reconstituted with 105 human CD34+ fetal liver cells by intrahepatic injection. The humanization of key cytokines should be important for the functional maturation of myeloid cells (Rathinam et al., 2011; Rongvaux et al., 2011, 2014; Willinger et al., 2011). However, the introduction of homozygous KitWv mutations was sufficient for reconstituted myeloid cells to maturate morphologically and to express genes related to their functions. It will be of interest to test whether the BRGSKWv/Wv mouse model can further improve human multi-lineage reconstitution potential by humanization of key cytokines. In summary, we introduced the loss-of-function KitWv mutation into the BRGS mouse strain and achieved a highly efficient, long-term, and multi-lineage engraftment of human HSCs. This line can reconstitute robust human erythropoiesis and thrombopoiesis without exogenous human cytokine support. The BRGSKWv/Wv mouse line is a useful tool to help increase our understanding of the biology of human multi-lineage hematopoiesis and a variety of malignant hematopoietic disorders.
Experimental Procedures
Author Contributions
Introduction The cerebral cortex is the center of the mammalian ci-1033 and provides the structural basis for complex perceptual and cognitive functions. The formation of the cortex relies on the expansion of neural progenitor cells (NPCs) and the subsequent generation of postmitotic neurons. Recent studies have shed light on neurogenesis, the process that underlies expansion of the neocortex whereby NPCs generate neurons. It has been reported that numerous immune proteins are expressed in neural stem cells, suggesting that immune signaling could be involved in the process of neurogenesis (Carpentier and Palmer, 2009). For a better understanding of this new role of immune proteins in brain development and function, it is first necessary to have a basic understanding of their known functions. Due to the existence of the blood-brain barrier and the immunosuppressive microenvironment, the CNS has been traditionally considered an immune-privileged organ (Sallusto et al., 2012). It has been reported that immune proteins classically thought to have specific immune function such as cytokines, major histocompatibility complex class I molecules, and T cell receptor subunits, are also expressed in the regions of the CNS (Boulanger, 2009; Komal et al., 2014; Syken and Shatz, 2003). Immune molecules play essential roles in various aspects throughout neural development of the CNS (Bauer et al., 2007; Boulanger, 2009). However, the expression, function, and mechanisms of action for the large majority of immune molecules in normal brain development have not yet been studied. Monocyte chemoattractant protein (MCP)-1-induced protein 1 (MCPIP1) is a recently identified protein harboring a CCCH-type zinc-finger domain (Liang et al., 2008; Xu et al., 2012). It is encoded by the ZC3H12A (zinc-finger CCCH-type containing 12A) gene, which is expressed in interleukin-1β (IL-1β)-induced human monocyte-derived macrophages and MCP-1-stimulated human peripheral blood monocytes (Skalniak et al., 2009; Zhou et al., 2006). MCPIP1 is necessary to inhibit unwanted immune reactions mediated by T cells through destabilizing a set of mRNAs (Uehata et al., 2013). Its deficiency leads to a complex phenotype involving severe anemia, severe inflammatory response, autoimmune response, and premature death (Liang et al., 2010; Matsushita et al., 2009). Structural studies of MCPIP1 reveal that the N-terminal conserved domain shows a PilT N-terminus-like RNase structure, providing further evidence that MCPIP1 has RNase activity. Recently, several studies have focused on the RNase activity of MCPIP1, which targets the mRNAs for IL-6, IL-1β (Matsushita et al., 2009; Mizgalska et al., 2009), and pre-microRNAs (Suzuki et al., 2011). The functional diversity and the RNase structure of MCPIP1 make it an attractive candidate as an immune regulator that mediates normal brain development.