Dr. Mina Bissell
Oct. 17, 2007
Erlanger Auditorium

2


Extra Cellular: outside the cell
Matrix: structure made from a network of
interacting components

The ECM is composed o...
4








Act as structural support to maintain cell organization and
integrity (epithelial tubes; mucosal lining of gu...
6
Types of ECMs
• Basement membrane (basal lamina)
– Epithelia, endothelia, muscle, fat,
nerves

• Elastic fibers
– Skin, lu...






Integrins
Dystroglycan
Syndecans
Muscle-Specific kinase (MuSK)
Others

8








Collagens
Proteoglycans

◦ Perlecan, aggrecan, agrin, collagen XVIII

Hyaluronan (no protein core)
Large Gly...




Most ECM proteins are large, modular,
multidomain glycosylated or glycanated
proteins
Some domains recur in
differen...




Specialized layers of extracellular matrix
surrounding or adjacent to all epithelia,
endothelia, peripheral nerves, ...
Fredrik Skarstedt and Carrie Phillips
12
13




In general, basement membranes appear very
similar to each other by EM.
But all are not alike!
There is a wealth of...
Kidney Basement Membranes

Laminin

2

Laminin

1
15







Collagen IV 6 chains form α chain
heterotrimers
Laminin 12 chains form several α-β-γ
heterotrimers
Entactin/Nid...






A family of fibrous proteins found in all
multicellular animals
They are secreted by connective tissue cells,
as ...
18
19




Collagen is highly cross-linked in tissues
where tensile strength is required such as
Achilles tendon
If cross-linki...
21


Collagen I

◦ Osteogenesis imperfecta
◦ Ehlers-Danlos syndrome type VII



Collagen II

◦ Multiple diseases of cartila...
Vanacore et al., Science 2009

23


COL4A1 mutations
◦ Small vessel disease/retinal
vascular tortuosity
◦ Hemorrhagic stroke
◦ Porencephaly
Kidney Glomerul...
Collagen Crosslinking
 If crosslinking is

inhibited (Lysyl
hydroxylase mutations;
vitamin C deficiency),
collagenous tis...







Liver spots on skin, spongy
gums, bleeding from mucous
membranes, depression,
immobility
Vitamin C deficiency
A...





At least four types of osteogenesis imperfecta
Type I osteogenesis imperfecta is the mildest
form of the conditio...
Clinical:
Ranges in severity from mild to perinatal lethal
bone fragility, short stature, bone deformities, teeth
abnormal...
•

Mutations in the COL1A1 and COL1A2 genes
cause OI

•

These mutations typically interfere with the
assembly of type I c...
30
Heterotrimers are composed of
one , one , and one chain.








400 to 800 kDa cruciform, Y, or rodshaped macromolec...






Laminin chains assemble
into trimers in the ER and
are secreted as trimers
into the extracellular
space.
Full-siz...
Involves LG domains and receptors on the surface of cells.
Results in laminin polymerization and signal transduction.
33
Lama1, Lamb1, Lamc1: Peri-implantation lethality (M)
Lama2: Congenital muscular dystrophy (M, H)
Lama3, Lamb3, Lamc2: Junc...
Major steps underlying the
assembly of microfibrils and
elastic fibers

Ramirez, F. et al. Physiol. Genomics 19: 151-154 2...
Fibrillin-1

Pro
RGD

Fibrillin
-2

Gly
RGD

Fibrillin
-3

P/G

RGD

LTBP-1

Fibrillin-1

EGF

Pro

Fibrillin
-2

RGD

LTB...


Caused by dominant
Fibrillin-1 (FBN1)
mutations

◦ Haploinsufficiency is the
culprit





Skeletal, ocular, and
card...







Damage to the lung air sacs
(alveoli) that affects breathing
Macrophages induced to
“ingest” particles in smoke...
Thanks

for
your attention

39
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  • 1 = acinus;; 2 = Islet of Langerhans, 4 = blood vessels
  • Ecm

    1. 1. Dr. Mina Bissell Oct. 17, 2007 Erlanger Auditorium 2
    2. 2.  Extra Cellular: outside the cell Matrix: structure made from a network of interacting components The ECM is composed of an interlocking mesh of fibrous proteins and glycosaminoglycans (GAGs). Components of the ECM are produced intracellularly by resident cells, and secreted into the ECM via exocytosis. 3
    3. 3. 4
    4. 4.      Act as structural support to maintain cell organization and integrity (epithelial tubes; mucosal lining of gut; skeletal muscle fiber integrity) Compartmentalize tissues (pancreas: islets vs. exocrine component; skin: epidermis vs. dermis) Provide hardness to bone and teeth (collagen fibrils become mineralized) Present information to adjacent cells: ◦ Inherent signals (e.g., RGD motif in fibronectin) ◦ Bound signals (BMP7, TGF , FGF, SHH) Serve as a highway for cell migration during development (neural crest migration), in normal tissue maintenance (intestinal mucosa), and in injury or disease (wound healing; cancer) 5
    5. 5. 6
    6. 6. Types of ECMs • Basement membrane (basal lamina) – Epithelia, endothelia, muscle, fat, nerves • Elastic fibers – Skin, lung, large blood vessels • Stromal or interstitial matrix • Bone, tooth, and cartilage • Tendon and ligament 7
    7. 7.      Integrins Dystroglycan Syndecans Muscle-Specific kinase (MuSK) Others 8
    8. 8.       Collagens Proteoglycans ◦ Perlecan, aggrecan, agrin, collagen XVIII Hyaluronan (no protein core) Large Glycoproteins ◦ Laminins, nidogens, fibronectin, vitronectin Fibrillins, elastin, LTBPs, MAGPs, fibulins “Matricellular” Proteins ◦ SPARC, Thrombospondins, Osteopontin, tenascins 9
    9. 9.   Most ECM proteins are large, modular, multidomain glycosylated or glycanated proteins Some domains recur in different ECM proteins ◦ Fibronectin type III repeats ◦ Immunoglobulin repeats ◦ EGF-like repeats Perlecan 10
    10. 10.   Specialized layers of extracellular matrix surrounding or adjacent to all epithelia, endothelia, peripheral nerves, muscle cells, and fat cells Originally defined by electron microscopy as ribbon-like extracellular structures beneath epithelial cells 11
    11. 11. Fredrik Skarstedt and Carrie Phillips 12
    12. 12. 13
    13. 13.    In general, basement membranes appear very similar to each other by EM. But all are not alike! There is a wealth of molecular and functional heterogeneity among basement membranes, due primarily to isoform variations of basement membrane components. 14
    14. 14. Kidney Basement Membranes Laminin 2 Laminin 1 15
    15. 15.     Collagen IV 6 chains form α chain heterotrimers Laminin 12 chains form several α-β-γ heterotrimers Entactin/Nidogen 2 isoforms Sulfated proteoglycans Perlecan and Agrin are the major ones; Collagen XVIII is another 16
    16. 16.    A family of fibrous proteins found in all multicellular animals They are secreted by connective tissue cells, as well as by a variety of other cell types They are the most abundant proteins in mammals, constituting 25% of the total protein mass in these animals 17
    17. 17. 18
    18. 18. 19
    19. 19.   Collagen is highly cross-linked in tissues where tensile strength is required such as Achilles tendon If cross-linking is inhibited, the tensile strength of fibers is greatly reduced, collagenous tissues become fragile, and structures tend to tear (skin, tendon, and blood vessels) 20
    20. 20. 21
    21. 21.  Collagen I ◦ Osteogenesis imperfecta ◦ Ehlers-Danlos syndrome type VII  Collagen II ◦ Multiple diseases of cartilage  Collagen III ◦ Ehlers-Danlos syndrome type IV  Collagen IV ◦ Alport syndrome, stroke, hemorrhage, porencephaly  Collagen VII ◦ Dystrophic epidermolysis bullosa (skin blistering) 22
    22. 22. Vanacore et al., Science 2009 23
    23. 23.  COL4A1 mutations ◦ Small vessel disease/retinal vascular tortuosity ◦ Hemorrhagic stroke ◦ Porencephaly Kidney Glomerular BM ◦ HANAC syndrome  COL4A3/A4/A5 mutations ◦ Alport syndrome/hereditary glomerulonephritis 24
    24. 24. Collagen Crosslinking  If crosslinking is inhibited (Lysyl hydroxylase mutations; vitamin C deficiency), collagenous tissues become fragile, and structures such as skin, tendons, and blood vessels tend to tear. There are also many bone manifestations of under-crosslinked collagen. 25
    25. 25.     Liver spots on skin, spongy gums, bleeding from mucous membranes, depression, immobility Vitamin C deficiency Ascorbate is required for prolyl hydroxylase and lysyl hydroxylase activities Acquired disease of fibrillar collagen Illustration from Man-of-War by Stephen Biesty (Dorling-Kindersley, NY, 1993) 26
    26. 26.     At least four types of osteogenesis imperfecta Type I osteogenesis imperfecta is the mildest form of the condition Type II is the most severe results in death in utero or shortly after birth Milder forms generate a severe crippling disease 27
    27. 27. Clinical: Ranges in severity from mild to perinatal lethal bone fragility, short stature, bone deformities, teeth abnormalities, gray-blue sclerae, hearing loss Biochemical: reduced and/or abnormal type I collagen Molecular: mutations in either type I collagen gene, COL1A1 or COL1A2, resulting in haploinsufficiency or disruption of the triple helical domain (dominant negative: glycine substitutions most common) 28
    28. 28. • Mutations in the COL1A1 and COL1A2 genes cause OI • These mutations typically interfere with the assembly of type I collagen molecules • • A defect in the structure of type I collagen weakens connective tissues, particularly bone, resulting in the characteristic features of OI OI types I, II, and IV have an autosomal dominant pattern of inheritance, which means one copy of the altered gene in each cell is sufficient to cause the condition 29
    29. 29. 30
    30. 30. Heterotrimers are composed of one , one , and one chain.      400 to 800 kDa cruciform, Y, or rodshaped macromolecules. Major glycoprotein of basement membranes—it’s required! Chains are evolutionarily related. 5 alpha, 4 beta, and 3 gamma chains are known. They assemble with each other non-randomly. 15 heterotrimers described to date. LM-521 31
    31. 31.    Laminin chains assemble into trimers in the ER and are secreted as trimers into the extracellular space. Full-sized laminin trimers can self-polymerize into a macromolecular network through short arm-short arm interactions. The chain LG domain is left free for interactions with cellular receptors. 32
    32. 32. Involves LG domains and receptors on the surface of cells. Results in laminin polymerization and signal transduction. 33
    33. 33. Lama1, Lamb1, Lamc1: Peri-implantation lethality (M) Lama2: Congenital muscular dystrophy (M, H) Lama3, Lamb3, Lamc2: Junctional epidermolysis bullosa (skin blistering) (M, H) Lama4: Mild bleeding disorder, moto-nerve terminal defects (M); cardiac and endothelial defects (H) Lama5: Neural tube closure, placenta, digit septation, lung, kidney, tooth, salivary gland defects (M) Lamb2: Neuromuscular junction and kidney filtration defects (M); Iris muscle, neuromuscular, kidney filtration defects (H; Pierson syndrome) Lamc3: Brain malformations, autism spectrum disorder? (H) 34
    34. 34. Major steps underlying the assembly of microfibrils and elastic fibers Ramirez, F. et al. Physiol. Genomics 19: 151-154 2004; 35 doi:10.1152/physiolgenomics.00092.2004 Physiological Society Copyright ©2004 American
    35. 35. Fibrillin-1 Pro RGD Fibrillin -2 Gly RGD Fibrillin -3 P/G RGD LTBP-1 Fibrillin-1 EGF Pro Fibrillin -2 RGD LTBP-2 Gly Fibrillin -3 P/G EGF--Ca Binding 8-Cys (CCC) Hybrid (CC) Unique Glycosylation (potential) RGD RGD LTBP-3 RGD LTBP-4 LTBP-1 RGD EGF RGD LTBP-2  RGD EGF--Ca Binding 8-Cys (CCC) Hybrid (CC) Unique Glycosylation (potential) Large glycoproteins (~350 kDa) whose LTBP-3 primary structures are dominated by LTBP-4 cbEGF domains that, in the presence of Ca2+, adopt a rodlike structure RGD 36
    36. 36.  Caused by dominant Fibrillin-1 (FBN1) mutations ◦ Haploinsufficiency is the culprit    Skeletal, ocular, and cardiovascular defects Deficiency of elastinassociated microfibrils Syndrome may result from alterations in TGF signaling, rather than purely structural changes in microfibrils 37
    37. 37.     Damage to the lung air sacs (alveoli) that affects breathing Macrophages induced to “ingest” particles in smoke also secrete proteases that degrade elastic fibers Loss of lung elasticity makes exhalation difficult Increased alveolar size reduces the surface area for gas exchange 38
    38. 38. Thanks for your attention 39
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