Noncanonical Transforming Growth Factor β (TGFβ) Signaling in Cranial Neural Crest Cells Causes Tongue Muscle Developmental Defects
Noncanonical Transforming Growth Factor β (TGFβ) Signaling in Cranial Neural Crest Cells Causes Tongue Muscle Developmental Defects
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DOI：
10.1074/jbc.m113.493551
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发表时间：
2013-10-11
影响因子：
4.8
通讯作者：
Chai, Yang
中科院分区：
文献类型：
--
作者：
Iwata, Jun-ichi;Suzuki, Akiko;Chai, Yang
小舌症是人类的一种先天性出生缺陷，对生活质量产生不利影响。在脊椎动物中，舌肌来源于颅中胚层，而颅面区域的肌腱和结缔组织来源于颅神经嵴（CNC）细胞。小鼠CNC细胞中转化生长因子β（TGF β）II型受体（Tgfbr 2（fl/fl）; Wnt 1-Cre）的缺失导致舌发育期间颅中胚层和CNC细胞之间的细胞-细胞通讯失败导致小舌症。然而，目前尚不清楚CNC细胞中的TGF β信号如何调节舌发育过程中胚层来源的成肌细胞的命运。在这里，我们表明，在Tgfbr 2（fl/fl）的细胞质和核酪氨酸激酶1（ABL 1）级联激活; Wnt 1-Cre小鼠的结果在一个失败的CNC衍生的细胞分化，随后由TGF β介导的诱导生长因子的破坏和肌细胞增殖和分化活动的减少。在受影响的生长因子中，加入成纤维细胞生长因子4（FGF 4）和卵泡抑素（FST;骨形态发生蛋白（BMP）的拮抗剂）的中和抗体可以最有效地恢复Tgfbr 2（fl/fl）; Wnt 1-Cre小鼠舌中的细胞增殖、分化和肌细胞组织。因此，我们的数据表明，在舌发育过程中，CNC衍生的成纤维细胞通过TGF β介导的FGF和BMP信号转导调节中胚层衍生的成肌细胞的命运。
Microglossia is a congenital birth defect in humans and adversely impacts quality of life. In vertebrates, tongue muscle derives from the cranial mesoderm, whereas tendons and connective tissues in the craniofacial region originate from cranial neural crest (CNC) cells. Loss of transforming growth factor beta (TGF beta) type II receptor in CNC cells in mice (Tgfbr2(fl/fl); Wnt1-Cre) causes microglossia due to a failure of cell-cell communication between cranial mesoderm and CNC cells during tongue development. However, it is still unclear how TGF beta signaling in CNC cells regulates the fate of mesoderm-derived myoblasts during tongue development. Here we show that activation of the cytoplasmic and nuclear tyrosine kinase 1 (ABL1) cascade in Tgfbr2(fl/fl); Wnt1-Cre mice results in a failure of CNC-derived cell differentiation followed by a disruption of TGF beta-mediated induction of growth factors and reduction of myogenic cell proliferation and differentiation activities. Among the affected growth factors, the addition of fibroblast growth factor 4 (FGF4) and neutralizing antibody for follistatin (FST; an antagonist of bone morphogenetic protein (BMP)) could most efficiently restore cell proliferation, differentiation, and organization of muscle cells in the tongue of Tgfbr2(fl/fl); Wnt1-Cre mice. Thus, our data indicate that CNC-derived fibroblasts regulate the fate of mesoderm-derived myoblasts through TGF beta-mediated regulation of FGF and BMP signaling during tongue development.