Hedgehog signaling regulates the generation of ameloblast progenitors in the continuously growing mouse incisor.
In many organ systems such as the skin, gastrointestinal tract and hematopoietic system, homeostasis is dependent on the continuous generation of differentiated progeny from stem cells. The rodent incisor, unlike human teeth, grows throughout the life of the animal and provides a prime example of an organ that rapidly deteriorates if newly differentiated cells cease to form from adult stem cells. Hedgehog (Hh) signaling has been proposed to regulate self-renewal, survival, proliferation and/or differentiation of stem cells in several systems, but to date there is little evidence supporting a role for Hh signaling in adult stem cells. We used in vivo genetic lineage tracing to identify Hh-responsive stem cells in the mouse incisor and we show that sonic hedgehog (SHH), which is produced by the differentiating progeny of the stem cells, signals to several regions of the incisor. Using a hedgehog pathway inhibitor (HPI), we demonstrate that Hh signaling is not required for stem cell survival but is essential for the generation of ameloblasts, one of the major differentiated cell types in the tooth, from the stem cells. These results therefore reveal the existence of a positive-feedback loop in which differentiating progeny produce the signal that in turn allows them to be generated from stem cells.
Department of Orofacial Sciences, Program in Craniofacial and Mesenchymal Biology, UCSF, 513 Parnassus Avenue, San Francisco, CA 94143-0442, USA.
Kerstin
K
Seidel
Christina P
CP
Ahn
David
D
Lyons
Alexander
A
Nee
Kevin
K
Ting
Isaac
I
Brownell
Tim
T
Cao
Richard A D
RA
Carano
Tom
T
Curran
Markus
M
Schober
Elaine
E
Fuchs
Alexandra
A
Joyner
Gail R
GR
Martin
Frederic J
FJ
de Sauvage
Ophir D
OD
Klein
D053687:Adult Stem Cells / Q000378:metabolism*; D000565:Ameloblasts / Q000166:cytology* / Q000378:metabolism; D000818:Animals; D002454:Cell Differentiation; D004847:Epithelial Cells / Q000378:metabolism; D005260:Female; D053823:Hedgehog Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism*; D007180:Incisor / Q000166:cytology / Q000254:growth & development*; D051379:Mice / Q000502:physiology*; D015398:Signal Transduction
D053823:Hedgehog Proteins; C465570:Shh protein, mouse