Module III: Branching Morphogenesis

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Module III Branching Morphogenesis
Problem Nutrients/metabolites exchange,
product secretion.
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Module III Branching Morphogenesis
Problem Nutrients/metabolites exchange,
product secretion. Answer Tube
formation/expansion/modeling to increase
exchange surface.
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Module III Branching Morphogenesis
Problem Nutrients/metabolites exchange,
product secretion. Answer Tube
formation/expansion/modeling to increase
exchange surface.
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Organs involve branching morphogenesis
Vasculature Lung (fly trachea and air
sacs) Kidney Lacrimal gland Mammary
gland Salivary gland Prostate
gland Pancreas
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Organs involve branching morphogenesis
Vasculature Lung (fly trachea and air
sacs) Kidney Lacrimal gland Mammary
gland Salivary gland Prostate
gland Pancreas
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Problems related to branching morphogenesis
Tube formation

• Form different tube types

Branch/grow
Terminal differentiation
Remodling/regeneration
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Problems related to branching morphogenesis
Tube formation

• Form different tube types
• Branch initiation
• Branch enlongation
• Branch reiteration

Branch/grow
Terminal differentiation
Remodling/regeneration
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Problems related to branching morphogenesis
Tube formation

• Form different tube types
• Branch initiation
• Branch enlongation
• Branch reiteration
• Progenitor maintenance vs. differentiation

Branch/grow
Terminal differentiation
Remodling/regeneration
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Problems related to branching morphogenesis
Tube formation

• Form different tube types
• Branch initiation
• Branch enlongation
• Branch reiteration
• Progenitor maintenance vs. differentiation
• Cellular origin/controlled division/differentiatio
  n.

Branch/grow
Terminal differentiation
Remodling/regeneration
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Problems related to branching morphogenesis
Tube formation

• Signaling
• ECM.

Branch/grow
Terminal differentiation
Remodling/regeneration
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• Form different tube types 5 classes

(Lubarsky and Krasnow, 2003)
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• Form different tube types 5 classes

(neural tube)
(Lubarsky and Krasnow, 2003)
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• Form different tube types 5 classes

(Lubarsky and Krasnow, 2003)
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• Form different tube types 5 classes

(lung, fly trachea, and most 2nd brnaches)
(Lubarsky and Krasnow, 2003)
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• Form different tube types 5 classes

(Lubarsky and Krasnow, 2003)
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• Form different tube types 5 classes

(salivary gland, proamnionic cavity)
(Lubarsky and Krasnow, 2003)
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• Form different tube types 5 classes

(Lubarsky and Krasnow, 2003)
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• Form different tube types 5 classes

(pancreas, c. elgans, zebrafish gut, vesseles)
(Lubarsky and Krasnow, 2003)
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• Form different tube types 5 classes

(Fly 2nd trachea, c elegans secretory cell)
(Lubarsky and Krasnow, 2003)
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2. Bud initiation spatial and temporal control
A
P
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2. Bud initiation spatial and temporal control
A
or
P
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2. Bud initiation spatial and temporal control
A
or
P
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2. Bud initiation spatial and temporal control
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2. Bud initiation spatial and temporal control
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2. Bud initiation spatial and temporal control
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2. Bud initiation spatial and temporal control
Cells with highest FGFR lead
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3. Bud enlongation role of the tip cells
Cells with highest FGFR lead
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3. Bud enlongation role of the tip cells

• Lead the branching process
• Progenitor for cell proliferation

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3. Bud enlongation role of the tip cells

• Lead the branching process
• Progenitor for cell proliferation

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3. Bud enlongation role of the tip cells

• Lead the branching process
• Progenitor for cell proliferation
• Initiating 2ndary branch?

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4. Branch reiteration epithelial-mesenchyme
cross-talk
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4. Branch reiteration epithelial-mesenchyme
cross-talk
?
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4. Branch reiteration epithelial-mesenchyme
cross-talk
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4. Branch reiteration epithelial-mesenchyme
cross-talk
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5. Terminal differentiation and size control
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5. Terminal differentiation and size control
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5. Terminal differentiation and size control
Notch signaling in pancreas
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5. Terminal differentiation and size control
Notch signaling in pancreas
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5. Terminal differentiation and size control
Notch signaling in pancreas
Notch ligands Notch Hes1
TFs (Ngns)
differentiation
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5. Terminal differentiation and size control
Notch signaling in pancreas inactivation
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5. Terminal differentiation and size control
Notch signaling in pancreas inactivation
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5. Terminal differentiation and size control
Size control
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6. Branch maintenance and remodeling
Mammary gland only present in mammals, but share
many signaling molecules used by other glands.
Stage I (1st trimester) not hormone
dependent Stage II (puberty) estrogen and
receptor Stage III (adults) progesterone and
receptor
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6. Branch maintenance and remodeling
Embryonic newly born
puberty
A puberty pregnancy
involution
(Robinson, 2001)
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6. Branch maintenance and remodeling
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6. Branch maintenance and remodeling
A, instructive signal of mesenchyme
epidermis

Mes.
epidermis
Mes.
(Cunha et al., 1995)
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6. Branch maintenance and remodeling
B, interaction between epithelial and
mesenchymal cells
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6. Branch maintenance and remodeling
Remodeling for each cycle
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6. Branch maintenance and remodeling
Remodeling for each cycle involvement of stem
cells? Do they exist? Where are they? Can they
be isolated?
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6. Branch maintenance and remodeling
Remodeling for each cycle involvement of stem
cells?
(Smith, 2005)
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6. Branch maintenance and remodeling
Remodeling for each cycle involvement of stem
cells?
Estrogen R progesterone R
(Smith, 2005)
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6. Branch maintenance and remodeling
Remodeling for each cycle involvement of stem
cells?
Fig. 5. The progeny of parity-induced mammary
epithelial cells marked by the expression of
ß-galactosidase (blue) included LREC that were
doubly labeled by 5BrdU and 3HtdR (arrows) in
mammary transplant outgrowths in the cleared fat
pads of doubly pulsed female hosts. This
indicated that during the process of expansive
self-renewal some of these cells become
asymmetrically dividing LREC. The red brackets
outline the region of the image where the plane
of section is tangential to the long axis of the
duct, thus exposing the suprabasal epithelial
layer. Scale bar 10 µm.
(Smith, 2005)
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6. Branch maintenance and remodeling
Remodeling for each cycle involvement of stem
cells?
(Shakleton et al., 2006)
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6. Branch maintenance and remodeling
Remodeling for each cycle involvement of stem
cells?
(Shakleton et al., 2006)
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6. Branch maintenance and remodeling
Remodeling for each cycle involvement of stem
cells?
(Shakleton et al., 2006)
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7. Signaling molecules
FGF Hedgehog, TGFbeta/BMP, Wnt, Notch, Other
growth factor receptors,
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8. ECM in branching morphogenesis
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8. ECM in branching morphogenesis
Fibronectin expression
Submandibular gland. From Sakai et al. 2003
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8. ECM in branching morphogenesis
(Protein)
Submandibular gland. From Sakai et al. 2003
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8. ECM in branching morphogenesis
Submandibular gland. From Sakai et al. 2003
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8. ECM in branching morphogenesis
Glycosaminoglycan, laminins, and
collagens Enzymes required for ECM remodeling
metalloproteinase, glycosaminoglycan degrading
enzymes, Collagenase.
Review by Hoffman, 2006
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8. ECM in branching morphogenesis
control
collagenase
collagenase inhibitor
Salivary gland culture
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Summary

• Multiple factors are involved in branching
  morphogenesis
• Common mechanisms exist for all branching organs
• Similar mechanisms operate in multiple round of
  branching
• Branching is coupled with cell proliferation/diffe
  rentiation in some systems
• Stem cells are involved in regeneration and
  remodeling.

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Questions

• The nature of particular signals for each organ
• The execution of particular signals
• The integration and execution of multiple
  signals
• The temporal control
• The cellular behaviors during branch---progenitor
  activity maintenance vs. terminal
  differentiation
• Correlate cell behaviors with specific signals
• Stem cell reactivation/morphogenesis during
  remodeling.