MT1-MMP regulates central nervous system development through Notch signaling

The central nervous system (CNS) development is a highly organized process involving cell proliferation, cell death and cell migration. The mechanisms that goven this process are complex and remain one of the most challenging question in neurobiology. Notch signaling is among the most important pathways that participate in the CNS development. The absence of Notch signaling causes precocious neuronal differentiation and reduced generation of neurons. On the contrary, activation of Notch signaling leads to the maintenance of embryonic telencephalic cells in an undifferentiated status. Moreover, Notch signaling first inhibits neuron fate while promotes glial fate and later promotes astroglia production and suppresses oligodendroglia differentiation. Membrane-type 1 matrix metalloproteinase (MT1-MMP) is the first identified membrane tethered matrix metalloproteinase which is best and first known for its role in tumor metastasis. Since then, it has been shown that MT1-MMP is important for proper generation of many tissues and organs, such as the skeleton, lung or B-cells. In addition, MT1-MMP is also involved in several pathological conditions, particularly in cancer. It functions in extracellular matrix (ECM) turnover and membrane-anchored molecules cleavage hence it is important for cell-ECM interactions, soluble molecules releasing and cell signaling regulation. Indeed, recent findings showed that MT1-MMP sheds DLL1 to negatively regulate Notch signaling in bone marrow stroma cells (BMSCs) which ultimately causes defective B-cell development in MT1-MMP knockout mice. However, the function of MT1-MMP during CNS development has never been studied before. In this study, I hypothesize that MT1-MMP may be involved in CNS development and, together with the recent findings in our lab, its function may be mediated by Notch signaling. The expression pattern of MT1-MMP in CNS was for the first time described in this study. Loss of MT1-MMP affects CNS development with impaired ventricle development in forebrain and neural tube closure problem in the midbrain at embryonic stage. At postnatal stage, MT1-MMP loss causes enlarged lateral ventricle (LV) size, altered cortex pattern, accelerated cell death and defective differentiation into OLs. Furthermore, increased amount of Nestin+/GFAP+ cells in the MT1-MMP knockout as well as the larger size of the MT1-MMP-/- neurospheres were found, indicating that MT1-MMP participates in neural stem cell (NSC) and neural progenitor cell (NPC) proliferation, self-renewal and/or survival. DAPT treatment can rescue the phenotype of MT1-MMP-/- neurospheres and thus these results suggest that MT1-MMP controls CNS development through at least the regulation of Notch signaling. Notch signaling was demonstrated to be abnormally activated at both embryonic and postnatal stages as well as either in vivo or in vitro in the absence of MT1-MMP. Additional functions of MT1-MMP in the ECM and neuroepithelial cell (NEC) polarity can also be considered. The amount and distribution of the ECM component fibronectin and its main receptor β1-integrin are affected by loss of MT1-MMP. Besides, less primary cilium and cell surface accumulation of β-catenin and N-cadherin occurs in the MT1-MMP-/- neuroepithelium. In short, I found that MT1-MMP regulates Notch signaling in CNS. Indeed, loss of MT1-MMP causes abnormally activated Notch signaling that contributes to defective CNS development.published_or_final_versionBiochemistryDoctoralDoctor of Philosoph