Runx3 and Runx1 are required for CD8 T cell development during thymopoiesis

Abstract

The RUNX transcription factors are important regulators of lineagespecific gene expression. RUNX are bifunctional, acting both as activators and repressors of tissue-specific target genes. Recently, we have demonstrated that Runx3 is a neurogenic transcription factor, which regulates development and survival of proprioceptive neurons in dorsal root ganglia. Here we report that Runx3 and Runx1 are highly expressed in thymic medulla and cortex, respectively, and function in development of CD8 T cells during thymopoiesis. Runx3-deficient (Runx3 KO) mice display abnormalities in CD4 expression during lineage decisions and impairment of CD8 T cell maturation in the thymus. A large proportion of Runx3 KO peripheral CD8 T cells also expressed CD4, and in contrast to wild-type, their proliferation ability was largely reduced. In addition, the in vitro cytotoxic activity of alloimmunized peritoneal exudate lymphocytes was significantly lower in Runx3 KO compared with WT mice. In a compound mutant mouse, null for Runx3 and heterozygous for Runx1 (Runx3 ؊/؊ ;Runx1 ؉/؊ ), all peripheral CD8 T cells also expressed CD4, resulting in a complete lack of single-positive CD8 ؉ T cells in the spleen. The results provide information on the role of Runx3 and Runx1 in thymopoiesis and suggest that both act as transcriptional repressors of CD4 expression during T cell lineage decisions.T he mammalian RUNX3͞AML2 gene resides on human chromosome 1p36.1 and mouse chromosome 4, respectively (1-4). It belongs to the RUNX family of transcription factors, which contains three genes. The two other family members, RUNX1 and RUNX2, play fundamental roles in hematopoietic and osteogenic lineage-specific gene expression, and when mutated, are associated with human diseases (5, 6). The three RUNX genes are regulated at the transcriptional level by two promoters, and at the translational level by internal ribosome entry site (IRES)-and cap-dependent translation control (7-14). The gene products of RUNX bind to the same DNA motif and activate or repress transcription of target genes through recruitment of common transcriptional modulators (15)(16)(17)(18). Despite this occurrence, each of the Runx genes has well defined biological functions reflected in a different expression pattern of the genes (19-23) and distinct phenotypes of the corresponding knockout mice (6,(24)(25)(26)(27).During mouse embryogenesis Runx3 is expressed in hematopoietic organs, epidermal appendages, developing bones, and sensory ganglia (20). Studies in knockout (KO) mice revealed that Runx3 is a neurogenic-specific transcription factor required for development and survival of TrkC neurons in the dorsal root ganglia. In the absence of Runx3 these neurons die, leading to disruption of the stretch reflex neuronal circuit, and consequently to severe ataxia (25,26). Intriguingly, in one strain of Runx3 KO, the gastric mucosa of newborn mice exhibits hyperplasia due to stimulated proliferation and suppressed apoptosis of stomach epithelial cells (27).It has previously been reporte...

Runx2 deletion in smooth muscle cells inhibits vascular osteochondrogenesis and calcification but not atherosclerotic lesion formation

“…21 These findings are likely explained by the truncated Runx2 protein acting via a dominant negative effect 42,45 on the Runt-related family members in addition to Runx2, especially Runx1 and Runx3 that share the same highly conserved Runt DNA binding domain and are involved in regulating monocyte/macrophage biology. [46][47][48] Along these lines, recent studies have shown transdifferentiation of SMCs into a lipid-loaded, foam cell-like state during atherosclerosis. [49][50][51] These studies suggest that SMCs may not only contribute to fibrous cap formation and calcification but also directly participate in the process of atheroma formation through macrophage foam cell formation, accounting for $18-40% Mac2/CD68-positive cells observed in human and mouse atherosclerotic lesions.…”

“…[49][50][51] These studies suggest that SMCs may not only contribute to fibrous cap formation and calcification but also directly participate in the process of atheroma formation through macrophage foam cell formation, accounting for $18-40% Mac2/CD68-positive cells observed in human and mouse atherosclerotic lesions. 49 to control myeloid differentiation necessary for monocyte/macrophage and osteoclast formation, [46][47][48] their transcriptional activities may also be critical in controlling the SMC to macrophage/foam cell-like differentiation. Therefore, the dominant negative effect of truncated Runx2 in both bone marrow-derived cells and SMCs could act synergistically to prevent atheromatous plaque formation as seen in the Sun et al 21 study, though a detailed mechanism would require further investigation.…”

CCR7 Expression in Developing Thymocytes Is Linked to the CD4 versus CD8 Lineage Decision

“…Other transcription factors have also been implicated in CD4/CD8-lineage commitment, including GATA-3, which is required for CD4-lineage development (5-7), TOX that can direct CD8-lineage development (8), and Runx3, which is involved in silencing CD4 gene expression in CD8-lineage cells (9,10).…”

Runx3 is required for the differentiation of lung epithelial cells and suppression of lung cancer

“…RUNX1 and RUNX2 are essential for hematopoiesis and osteogenesis, respectively, and are often mutated in leukemia and bone disease (Okuda et al, 1996;Lee et al, 1997;Look, 1997;Mundlos and Olsen, 1997;Otto et al, 1997). RUNX3 is involved in neurogenesis Levanon et al, 2002) and thymopoiesis (Taniuchi et al, 2002;Woolf et al, 2003), and it functions as a tumor suppressor in gastric cancer (Guo et al, 2002;Li et al, 2002;Kim et al, 2005b;Ito et al, 2008). RUNX3 regulates target gene expression by forming a complex with Smads, the transducer of TGF-b signaling.…”