The L6 domain tetraspanin Tm4sf4 regulates endocrine pancreas differentiation and directed cell migration
The L6 domain tetraspanin Tm4sf4 regulates endocrine pancreas differentiation and directed cell migration
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DOI：
10.1242/dev.058693
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发表时间：
2011-08-01
期刊：
影响因子：
4.6
通讯作者：
Sussel, Lori
中科院分区：
文献类型：
--
作者：
Anderson, Keith R.;Singer, Ruth A.;Sussel, Lori
同源域转录因子Nkx2.2对于胰腺发育和胰岛细胞类型分化是必需的。我们已经鉴定了Tm 4sf 4，一种L 6结构域四跨膜蛋白家族成员，作为Nkx2.2的转录靶点，其在Nkx2.2（-/-）小鼠的胰腺发育过程中大大上调。四跨膜蛋白和L 6结构域蛋白募集其他膜受体形成活性信号传导中心，协调细胞粘附、迁移和分化等过程。在这项研究中，我们确定了Tm 4sf 4定位于导管上皮区室，并在Ngn 3（+）胰岛祖细胞中突出。我们还建立了胰腺tm 4sf 4的表达和调节Nkx2.2是保守的斑马鱼发育过程中。在斑马鱼中进行的功能丧失研究显示，tm 4sf 4抑制α和β细胞的特化，但对e细胞的命运是必需的。因此，Tm 4sf 4功能输出与Nkx2.2的功能输出相反。进一步研究Tm 4sf 4在体外细胞水平的功能表明，Tm 4sf 4抑制Rho激活的细胞迁移和肌动蛋白组织在ROCK独立的方式。我们提出Nkx2.2的主要作用是抑制内分泌祖细胞中的Tm 4sf 4，从而允许分层、迁移和/或适当的细胞命运决定。Tm 4sf 4在内分泌分化过程中的作用的鉴定提供了对胰岛祖细胞行为和潜在的靶向再生机制的深入了解。
The homeodomain transcription factor Nkx2.2 is essential for pancreatic development and islet cell type differentiation. We have identified Tm4sf4, an L6 domain tetraspanin family member, as a transcriptional target of Nkx2.2 that is greatly upregulated during pancreas development in Nkx2.2(-/-) mice. Tetraspanins and L6 domain proteins recruit other membrane receptors to form active signaling centers that coordinate processes such as cell adhesion, migration and differentiation. In this study, we determined that Tm4sf4 is localized to the ductal epithelial compartment and is prominent in the Ngn3(+) islet progenitor cells. We also established that pancreatic tm4sf4 expression and regulation by Nkx2.2 is conserved during zebrafish development. Loss-of-function studies in zebrafish revealed that tm4sf4 inhibits alpha and beta cell specification, but is necessary for e cell fates. Thus, Tm4sf4 functional output opposes that of Nkx2.2. Further investigation of how Tm4sf4 functions at the cellular level in vitro showed that Tm4sf4 inhibits Rho-activated cell migration and actin organization in a ROCK-independent fashion. We propose that the primary role of Nkx2.2 is to inhibit Tm4sf4 in endocrine progenitor cells, allowing for delamination, migration and/or appropriate cell fate decisions. Identification of a role for Tm4sf4 during endocrine differentiation provides insight into islet progenitor cell behaviors and potential targetable regenerative mechanisms.