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Colin JamoraIFOM-inStem Joint Research Laboratory
Centre for Inflammation and Tissue HomeostasisInstitute for Stem Cell Biology and Regenerative Medicine
Organ Development and Regeneration:A Hairy Situation
University of Salento, Nov. 2014
How do organs form?
1. Break it down into simple “morphometric modules” and identify thedevelopmental signals that guide their formation
2. Describe the changes in cellular anatomy that occur during morphogenesis
3. Elucidate the molecular programs that underlie the changes in cell parameters:Shape, Polarity, Movement, Adhesion, Proliferation
Examples of Morphometric Modules Studied During Organogenesis
Tubulogenesis
Budding morphogenesis
Branching morphogenesis
Advantages of the skin/hair as a model organ system
Ability to easily culture adult stem/progenitor cells
Biochemical and cell biological techniques to elucidate intracellular signaling pathways
Ease of scoring defects (both mild and dramatic) in both transgenic and knockout mice
Not critical for the development and viability of the whole animalMice are viable until birth in the absence of epidermisLoss of hair does not impair the health of housed mice
Amenable to genetic manipulation to test in vivo function(s) of genes
In vivo:
In vitro:
2012 Nobel Prize: Reprogramming dermal fibroblasts into stem cells
Skin fibroblast
Pa/ent
Reprogramming Unknown gene/c
and epigene/c processes
Pluripotent stem cell
Disease Models (chemical + gene/c
screening)
“Personalized” Regenera/ve Medicine
(no rejec/on)
Nanog
Sox 2 Oct 3/4
The mammalian skin as a model system to study lineage determination
epidermal ectoderm
basement membrane
mesenchyme
Cellular Adhesion Molecules Maintain Epidermal Organization
Vaezi et al., Dev Cell 2002
E-cadherin/actin
Basal layer
Spinous layer
Granular layerStratum corneum
Budding morphogenesis initiates hair follicle development
E-cadherin
Adapted from S. Millar J. Invest. Derm. 2002
P-cadherin
Cadherin switchDevelopment: Gastrulation
Neural Crest FormationGenital Ridge Population
Disease: Metastasis
hair
Morphogenesis
Adult organ
liver lung mammarygland
tooth
Bud
Undifferentiatedepithelium
Adapted from Pispa & Thesleff Dev. Bio. 2003
Morphogen(s)/Extracellular Signal(s)
Transcription Factor
Target Gene
Phenotype/Cell Behavior
Strategy for elucidating the mechanisms regulating hair bud morphogenesis
Bone Morphogenic Protein (BMP) Signaling Pathway Regulates Lef Expression
(e.g. noggin, chordin, gremlin) Lef expressing cell
Wnt & Noggin produce a transcriptionally competent Lef1/ß-cat complex
TOP c-fos luciferaseTOP TOP
ß-catLef-1
* * *
Coupling Cell Fate Determination with Changes in Cell Morphology
Is E-cadherin a target of the Lef1/ß-catenin transcription complex ?
Possible Mechanisms for Lef1/ß-cat-mediated E-cadherin Repression
• Lef1/ß-cat functions as a transcriptional activator
ß-catLef1 Repressor
RepressorE-cadherin
ß-catLef1 E-cadherin
• Lef1/ß-cat functions as a transcriptional repressor
Morphogen
Transcription Factor
Target Gene ?
?Effector(s)
What is the Physiological Relevance of E-cadherin Dynamics?
(mes) (epi)
E-cadherin overexpression promotes epidermal differentiation
E-cadherin conditional null:C. Tinkle, T. Lechler, & E. Fuchs
PNAS 2004
(laminin)(K5)
wt Tg
K5
Budding Morphogenesis is Guided By A Network of Signals and Genes
?Morphogen
Transcription Factor
Effector
Gene
Noggin Wnt
Lef-1 ß-cat
E-cadherin
Polarity Differentiation Proliferation Motility
Snail
TGFß2
?
BM
Common Themes in Mammalian Stem Cell Systems
epidermal intestinal
bone marrow
From Moore and LemischkaScience 2006
Acknowledgements
Rolf Kemler Ralf Paus
Andrew McMahonRudolf GrosschedlRichard Harland
Antonio Garcia de HerrerosHans Clevers
Masatoshi TakeichiShinji Takada
Jamora LabLuke DenlyPedro LeeJoanne LeeCarol ChanJohn GibsonSamuel Lasse
Fuchs LabElaine Fuchs
Ram DasguptaPawel Kocienski
Members of the Fuchs lab