• This could influence the gene expression profile of the cells, especially in their extracellular matrix, which often provides physical support and a chemical barrier for the

  • [16] The protein becomes visible by immunostaining on day 15 during mouse development, independently from other basement membrane proteins, suggesting that it is simply a
    part of the ECM of developing chondrocytes, in addition to collagen II and other cartilage markers that are expressed starting on day 12.

  • The first study of perlecan expression during embryonal development found that the protein was first expressed during development of the cardiovascular system, and later correlates
    with maturation of the majority of tissues in the body, i.e.

  • In human coronary smooth muscle cells in culture, TGF-β1 signaling showed no effect on perlecan expression although it did upregulate other matrix constituents.

  • While studying the effect of proteoglycan composition on nephritic permselectivity, it was noted that puromycin treatment of human glomerular endothelial cells (HGEC) altered
    the sulfation level of GAG chains on proteoglycans such as perlecan, which in turn caused a decrease in the stability of the GAG chains.

  • [17] Signaling pathways and their effect on expression[edit] Signaling pathways function to elevate or decrease levels of transcription of genes, which in turn cause cells
    to change their gene expression profile.

  • One study examined the in vitro effects of pressure on global gene transcription using a microarray approach and a cell stretching system meant to simulate intraocular pressure
    in the lamina cribosa (connective tissue) of the optic nerve head.

  • By expressing a recombinant form of the N-terminal domain I of the protein and demonstrating that digestion of the peptide with either heparanase or chondroitinase did not
    lead to complete loss of the peptide’s activity, it was shown that chondroitin sulfate chains can be added to human perlecan.

  • As previously mentioned, to investigate the effect of brain inflammation on expression levels of perlecan, needle stab wounds were created in mice brains, and after inflammation
    and variable periods of recovery, mRNA and protein levels were assessed via in situ hybridization and immunostaining.

  • This difference between endothelial cells from the study in 2007 and the epithelial cell studied in these experiments is indicative of how varied the regulatory mechanisms
    of perlecan may be in different cell types.

  • [34] In the rat embryo, perlecan expression has been shown to increase in vascular smooth muscle cells (VSMCs) post e19 in fetal development.

  • The core protein mRNA levels of proteoglycans were not affected, thus the decrease in GAG chains was as a result of some other factor, which in this case turned out to be
    a decrease in expression of sulfate transferase enzymes, which play a key role in GAG biosynthesis.

  • In another study, hypoxia led to induction of genes associated with apoptosis and cell death, but repression of genes was not limited to proteins associated with a specific

  • [53] In the epidermal injury study, a wound spanning the depth of the epidermis was created in exon 3-negative mice and control mice, and in the knockout mice angiogenesis
    and the hallmarks of wound healing were slow to develop possibly due to decreased growth factor sequestration by the heparan sulfate-negative perlecan.

  • Cell stressors and their effect on expression[edit] Mechanical and chemical stress can damage basement membranes or the cells they support.

  • [67] This was first shown in colon cancer cell lines, and subsequently in cell lines of other tissue origins, but in each case intact STAT1 transcription factor was required
    for the signal to take effect.

  • These plaques induce a constant state of inflammation in areas of accumulation, leading to expression of certain inflammation-related gene products, some of which perpetuate
    the inflammation in the brain context.

  • In tissue engineered heart valves created by seeding myofibroblasts onto collagen type I followed by endothelial cells, heparan sulfate proteoglycan expression has been verified,
    although no distinction between syndecan and perlecan has been made in these tissues.

  • In vitro studies of TGF-β1 signaling and its effects on perlecan expression can have varying results in different cell types.

  • Function Perlecan is a key component of the extracellular matrix of cartilage[15] where it is essential for normal growth plate development and long bone growth.

  • This and perlecan’s role as endorepellin prompted one study into the nature of perlecan expression regulation by endothelial cells during hypoxic conditions.

  • Specific proteases act on the protein in the extracellular environment when cells have a reason to move or change their surroundings.

  • [77] A similar finding was shown in acetamenophin treatment of mice, where perlecan and other matrix components were heavily expressed in necrotic lesions of the liver.

  • The study showed that the exon 3 knockout mice had collapse of lens capsule integrity by postnatal week 3, indicating a role for the amino acids deleted from domain I of perlecan
    in maintaining lens capsule basement membrane integrity.

  • In this case, it seems that the molecule’s signaling function is the operative upregulated factor, especially due to the increase in sulfation of the heparan sulfate chains.

  • Perlecan is a potent inhibitor of smooth muscle cell proliferation and is thus thought to help maintain vascular homeostasis.

  • [70] When T84 intestinal epithelial cells are exposed to hypoxic conditions for 24 hours a significant increase in perlecan mRNA and protein production occurs.

  • Studies from gene knockout mice and human diseases have also revealed critical in vivo roles for perlecan in cartilage development[56] and neuromuscular junction activity.

  • Using a similar cell stretching mechanism to mimic arterial pressure, this investigation showed that perlecan production increased in response to mechanical strain.

  • This microvascular-specific regulation by VEGF165 raises the possibility that the anti-coagulant function of perlecan is a part of the damage-control process in brain endothelia.

  • A thorough study of perlecan expression during chick embryo development has shown that perlecan is present at the morula stage and for the rest of development, although expression
    can be transient and precisely timed in certain tissue predecessors.

  • Another system using a disorganized hydrated collagen I gel has been used to demonstrate that primary human corneal fibroblasts will eventually invade the gel and create a
    matrix consisting of collagen type I and perlecan, as well as several other sulfated matrix glycoproteins.

  • The perlecan transgenic mice, however, exhibited muscle hypertrophy,[55] indicating a role for perlecan in muscle development as well as in cartilage growth plate mediated
    long bone growth.

  • [52] This developmentally dynamic tissue showed a serious misregulation of extracellular matrix components including perlecan with TGF-β1 over expression.

  • Removal of HS chains may affect matrix organization and endothelial barrier function.

  • It could be that these endothelial cells merely downregulated transcription of many genes in response to hypoxic conditions.

  • A number of signaling molecules can effect changes in perlecan expression including the transforming growth factor-Beta (TGF-β), interleukin(IL) and vascular endothelial growth
    factor (VEGF) families of molecules.

  • Morpholinos were used to block translation of the perlecan mRNA in zebrafish embryos, as part of an investigation into perlecan function in skeletal and vascular development.

  • Spatio-temporal specificity in trans-activation of the perlecan gene during development is key to the maturation of basement membranes and thus to the complete separation
    of epithelia from endothelia and stroma.

  • [60] In vivo demonstration of the dynamic regulation of perlecan and its control by extracellular signaling pathways is critical to our understanding of the protein’s role
    in development.

  • [31] Expression Expression during development[edit] Timing of gene expression during development varies from tissue to tissue.

  • Addition of heparanase to cell culture of epithelia in basement membrane caused an increase in epithelial cell proliferation due to FGF-10 release.

  • This suggests that, in the exon 3 knockout, the remaining attachment sites for heparan sulfate on domains I and V available for FGF-2 binding[19] or the site on domain 3 available
    for FGF-18 binding[20] may be sufficient for normal long bone growth.

  • [14] Thus, perlecan core protein and HS chains could modulate matrix assembly, cell proliferation, lipoprotein binding and cell adhesion.

  • [40] Taken with the data,[41] that mice lacking the pln gene cannot maintain stable cartilage, it is apparent that perlecan is essential to the maturation and stability of
    cartilaginous structure.

  • Chemical damage to organs can affect not only the cell’s genetic and mechanical integrity but the extracellular matrix of the tissue.

  • In a mouse model of Alzheimer’s plaque formation, IL-1-alpha effects an increase in perlecan expression in response to brain injury.

  • [68] Presumably the loss of perlecan expression stems from downregulation of transcription via STAT1 transcription factor activity as shown previously.

  • [78] Expression in cell culture[edit] One of the resounding arguments against the validity of in vitro results of cell culture on 2D plastic plates is that the environment
    does not accurately reflect that of the cells in the organism.

  • These in vitro results are not necessarily representative of normal physiological interferon- γ concentrations, nor are the cytokine normally expressed widely but instead
    at very specific developmental timepoints.

  • The end effect of signaling pathways is exerted on the promoter of genes, which can include elements upstream or downstream of the transcriptional start site, some of which
    can exist inside of the transcribed gene itself.

  • [72] At the organismic level, mechanical stress has a profound impact on extracellular matrix integrity and probably causes induction of a number of ECM genes for repair and
    remodeling of ECM in tissue stroma and basement membranes.

  • [29] This proteolytic process may have significance in disease as a corresponding fragment was found in the urine of patients suffering end-stage renal failure[30] and in
    the amniotic fluid of pregnant women who have undergone premature rupture of the membrane.

  • [69] Under hypoxic conditions, this study found that perlecan expression by rat cardiac microvascular endothelial cells was decreased sixty-one percent compared to normal

  • This resulted in the cartilage-compromised phenotype previously discussed and loss of basement membrane integrity in a variety of tissues.

  • Later embryonic development is just as precisely regulated as pre-implantation development, and is more complicated due to differentiation of all tissues.

  • Perlecan is also a key component of the vascular extracellular matrix, where it interacts with a variety of other matrix components and helps to maintain the endothelial barrier

  • [38] Perlecan also showed nerve adhesive properties in a previous study, further suggesting that it may act in an attractive role in combination with laminin rather than a
    repulsive one.

  • [13] Although HS chains are not required for correct folding and secretion of the protein, lack of HS or decreased sulfation can decrease perlecan’s ability to interact with
    matrix proteins.

  • This is supported by a study showing that knockdown of perlecan production inhibits the final stages of chondrogenic differentiation in C3H10T1/2 fibroblasts in culture.

  • [80] This effect also led to a lack of hemidesmosomes in the developing tissue.

  • [39] Cartilage and bone development have proven to be dependent upon perlecan expression.

  • Perlecan isolated from developing growth plates has been shown to bind to FGF-2 via its heparan sulfate side chains,[19] and to FGF-18 via domain III of its core protein[20]
    and mediates their action on FGF receptors.

  • [54] The collagen type II promoter allowed perlecan expression in the extracellular matrix made by chondrocytes only but not in the basement membranes made by endothelial,
    epithelial or muscle cells.

  • It does seem counterintuitive that endothelial cells would proliferate less quickly due to loss of perlecan and its endorepellin subunit.

  • Perlecan was originally isolated from a tumor cell line and shown to be present in all native basement membranes.

  • Perlecan and laminin-1 appear to be important in this guidance pathway, although perlecan induction occurs slightly later than laminin-1.


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