Conditions Of The Adam10 Gene In Thymocyte Development, Nurturing And Adam10 Knockout Mice Regulation Of Notch Signaling Pathway

Notch signaling pathway regulates multiple stages of thymocyte development. Dysregulation of the pathway involves in T lymphoblastic leukemia and other diseases.Precise control of sequential proteolytic cleavage events of the Notch receptor release an intracellular fragment(ICN),which then activate the transcription of Notch target genes in nucleus.Previous studies in Drosophila showed kuzbanian (kuz) as an upstream activation of Notch.To test whether ADAM10,the mammalian homologue of KUZ,plays similar roles in Notch signaling pathway,we established a conditional knockout model of Adam10 in mice.Identical to the previously described Notch1 mutants,disruption of Adam10 in mouse thymocytes results in developmental defects such as reduced thymus size and decreases of total and DP thymocyte number.Furthermore,activation of Notch1 and its downstream target genes is blocked in Adam10 deficient thymocytes.Our study supports that ADAM10 is a major metalloprotease responsible for activation of Notch1 during thymocyte development.As a transmembrane protease,ADAM10 could be considered as a potential drug target for the treatment of diseases related with dysregulation of Notch signals.