Involvement of a matrix metalloproteinase in MIS-induced cell death during urogenital development.
Involvement of a matrix metalloproteinase in MIS-induced cell death during urogenital development.
复制标题
泌尿生殖发育过程中基质金属蛋白酶参与 MIS 诱导的细胞死亡。
作者：
Lori M. Roberts;J. Visser;H. Ingraham
苗勒管的细胞程序性死亡在正常的雄性性分化过程中消除了原始的雌性生殖道。苗勒管抑制物质（MIS或AMH）通过在苗勒管间充质中传播BMP样信号传导途径引发消退，最终导致苗勒管上皮细胞凋亡。目前，在这种发育事件中使用的旁分泌信号还不确定。我们已经确定了一个成员的基质金属蛋白酶基因家族，Mmp2，作为第一个候选靶基因下游的MIS级联作为旁分泌死亡因子在苗勒管退化。Mmp2表达在男性苗勒管间充质中显著升高，这与其在退行中的作用一致，但在女性苗勒管间充质中则不然。此外，Mmp2的这种性二态表达在缺乏MIS配体的小鼠中消失，这强烈表明Mmp2的表达受MIS信号传导的调节。使用大鼠器官生殖嵴器官培养，我们发现，抑制MMP 2活性防止MIS诱导的回归，而MMP 2的激活促进配体非依赖性苗勒管回归。最后，MMP2反义实验导致苗勒管消退的部分阻断。根据我们的研究结果，我们提出，类似于其他发展计划，选择性消除或重塑组织发生，局部诱导细胞外蛋白酶是至关重要的正常男性泌尿生殖系统的发展。
Programmed cell death of the Müllerian duct eliminates the primitive female reproductive tract during normal male sexual differentiation. Müllerian inhibiting substance (MIS or AMH) triggers regression by propagating a BMP-like signaling pathway in the Müllerian mesenchyme that culminates in apoptosis of the Müllerian duct epithelium. Presently, the paracrine signal(s) used in this developmental event are undefined. We have identified a member of the matrix metalloproteinase gene family, Mmp2, as one of the first candidate target genes downstream of the MIS cascade to function as a paracrine death factor in Müllerian duct regression. Consistent with a role in regression, Mmp2 expression was significantly elevated in male but not female Müllerian duct mesenchyme. Furthermore, this sexually dimorphic expression of Mmp2 was extinguished in mice lacking the MIS ligand, suggesting strongly that Mmp2 expression is regulated by MIS signaling. Using rat organ genital ridge organ cultures, we found that inhibition of MMP2 activity prevented MIS-induced regression, whereas activation of MMP2 promoted ligand-independent Müllerian duct regression. Finally, MMP2 antisense experiments resulted in partial blockage of Müllerian duct regression. Based on our findings, we propose that similar to other developmental programs where selective elimination or remodeling of tissues occurs, localized induction of extracellular proteinases is critical for normal male urogenital development.
大鼠苗勒管退化过程中纤连蛋白、层粘连蛋白、IV 型胶原和基底膜蛋白聚糖的变化模式。
影响因子：
2.7
作者：
Ikawa,H;Trelstad,RL;Hutson,JM;Manganaro,TF;Donahoe,PK
通讯作者：
Donahoe,PK
影响因子：
3.3
作者：
MEREDITH, JE;FAZELI, B;SCHWARTZ, MA
通讯作者：
SCHWARTZ, MA
影响因子：
10.5
作者：
Mishina, Y;Rey, R;Behringer, RR
通讯作者：
Behringer, RR