ABSTRACT
The elucidation of the cellular and molecular mechanisms governing the maturation of the central nervous system (CNS) is rapidly emerging. Cell-cell and cell-matrix interactions play critical roles in all phases of developmental tissue remodeling. Throughout development, an intricate balance between extracellular matrix synthesis and degradation is preserved by the opposing actions of matrix metalloproteinases (MMPs) and their specific inhibitors, the tissue inhibitors of metalloproteinases (TIMPs). Although recent evidence suggests that TIMPs exert diverse cell biological functions distinct from their MMP-inhibitory activities, few studies have investigated MMP or TIMP expression during CNS development. The present report analyzes the mRNA expression of the four known TIMPs throughout the course of embryonic and postnatal rat CNS development. The results clearly demonstrate the unique spatial distribution and temporal regulation of TIMP expression and suggest a distinct role for each TIMP during CNS development.
Subject(s)
Central Nervous System/embryology , Central Nervous System/metabolism , RNA, Messenger/genetics , RNA, Messenger/metabolism , Tissue Inhibitor of Metalloproteinases/genetics , Animals , Central Nervous System/growth & development , DNA, Complementary/genetics , Gene Expression Regulation, Developmental , In Situ Hybridization , Rats , Tissue Inhibitor of Metalloproteinase-1/genetics , Tissue Inhibitor of Metalloproteinase-2/genetics , Tissue Inhibitor of Metalloproteinase-3/genetics , Tissue Inhibitor of Metalloproteinase-4ABSTRACT
To preserve tissue integrity during the structural rearrangements that occur during central nervous system (CNS) development, an intricate balance between extracellular matrix (ECM) synthesis and degradation must be maintained. The matrix metalloproteinases (MMPs) are believed to be the main mediators of ECM degradation. Because MMPs function in the turnover of a broad-spectrum of ECM proteins their activity is tightly regulated by interaction with tissue inhibitors of metalloproteinases (TIMPs). Whereas the primary function of TIMPs is to inhibit MMP activity, evidence is mounting that TIMPs are multifunctional molecules that exert diverse cell biological functions distinct from their MMP-inhibitory activities. Although the role of MMPs and TIMPs in the morphogenesis of non-neural tissues has been investigated, to date few studies have analyzed MMP or TIMP expression during CNS development. In the present report, we demonstrate the regulation of Timp-3 mRNA expression throughout the course of CNS development. In particular, Timp-3 mRNA is expressed in embryonic ventricular zones and the postnatal subventricular zone (SVZ). In addition, Timp-3 is expressed in the rostral migratory steam (RMS) to the olfactory bulb in a pattern similar to the ECM proteoglycan brevican. These data suggest that TIMP-3 and brevican may act in concert to guide neuronal migration along the RMS.
