Department of Pediatrics, Division of Human Genetics, University of California, Irvine, California 92697, USA.
Stem Cells. 2012 Oct;30(10):2152-63. doi: 10.1002/stem.1187.
T-box 3 (Tbx3) is a member of the T-box family of genes. Mutations that result in the haploinsufficiency of TBX3 cause ulnar mammary syndrome in humans characterized by mammary gland hypoplasia as well as other congenital defects. In mice, homozygous mutations are embryonic lethal, suggesting that Tbx3 is essential for embryo development. Studies in mice have shown that Tbx3 is essential in the maintenance of mouse embryonic stem cell (ESC) self-renewal and in their differentiation into extraembryonic endoderm (ExEn). The role TBX3 plays in regulating human ESCs (hESCs) has not been explored. Since mouse and hESCs are known to represent distinct pluripotent states, it is important to address the role of TBX3 in hESC self-renewal and differentiation. Using overexpression and knockdown strategies, we found that TBX3 overexpression promotes hESC proliferation possibly by repressing the expression of both NFκBIB and p14(ARF) , known cell cycle regulators. During differentiation, TBX3 knockdown resulted in decreased neural rosette formation and in decreased expression of neuroepithelial and neuroectoderm markers (PAX6, LHX2, FOXG1, and RAX). Taken together, our data suggest a role for TBX3 in hESC proliferation and reveal an unrecognized novel role of TBX3 in promoting neuroepithelial differentiation. Our results suggest that TBX3 plays distinct roles in regulating self-renewal and differentiation in both hESCs and mouse ESCs.
T 盒转录因子 3（Tbx3）是 T 盒基因家族的成员。导致 Tbx3 杂合子功能缺失的突变会引起人类的尺侧乳腺综合征，其特征是乳腺发育不全以及其他先天性缺陷。在小鼠中，纯合突变是胚胎致死的，这表明 Tbx3 对于胚胎发育是必需的。小鼠研究表明，Tbx3 对于维持小鼠胚胎干细胞（ESC）自我更新和分化为胚外内胚层（ExEn）是必需的。TBX3 在调节人胚胎干细胞（hESC）中的作用尚未被探索。由于已知小鼠和 hESC 代表不同的多能状态，因此确定 TBX3 在 hESC 自我更新和分化中的作用非常重要。我们使用过表达和敲低策略发现，TBX3 过表达可能通过抑制 NFκBIB 和 p14(ARF) 的表达来促进 hESC 的增殖，NFκBIB 和 p14(ARF) 是已知的细胞周期调节剂。在分化过程中，TBX3 敲低导致神经玫瑰花结形成减少，神经上皮和神经外胚层标记物（PAX6、LHX2、FOXG1 和 RAX）的表达减少。总之，我们的数据表明 TBX3 在 hESC 增殖中起作用，并揭示了 TBX3 在促进神经上皮分化中的一个未被认识的新作用。我们的结果表明，TBX3 在调节 hESC 和小鼠 ESC 的自我更新和分化中发挥不同的作用。
