gamma-secretase functions through Notch signaling to maintain skin appendages but is not required for their patterning or initial morphogenesis.
The role of Notch signaling during skin development was analyzed using Msx2-Cre to create mosaic loss-of-function alleles with precise temporal and spatial resolution. We find that gamma-secretase is not involved in skin patterning or cell fate acquisition within the hair follicle. In its absence, however, inner root sheath cells fail to maintain their fates and by the end of the first growth phase, the epidermal differentiation program is activated in outer root sheath cells. This results in complete conversion of hair follicles to epidermal cysts that bears a striking resemblance to Nevus Comedonicus. Sebaceous glands also fail to form in gamma-secretase-deficient mice. Importantly, mice with compound loss of Notch genes in their skin phenocopy loss of gamma-secretase in all three lineages, demonstrating that Notch proteolysis accounts for the major signaling function of this enzyme in this organ and that both autonomous and nonautonomous Notch-dependent signals are involved.
Pan
Yonghua
Y
Department of Molecular Biology and Pharmacology, Division of Dermatology, Washington University School of Medicine, Box 8103, 660 South Euclid Avenue, St. Louis, MO 63110, USA.
Lin
Meei-Hua
MH
Tian
Xiaolin
X
Cheng
Hui-Teng
HT
Gridley
Thomas
T
Shen
Jie
J
Kopan
Raphael
R
D053829:Amyloid Precursor Protein Secretases; D000818:Animals; D016282:Aspartic Acid Endopeptidases; D019521:Body Patterning / Q000235:genetics*; D002454:Cell Differentiation; D019070:Cell Lineage; D010450:Endopeptidases / Q000378:metabolism*; D004814:Epidermal Cyst / Q000473:pathology; D017353:Gene Deletion; D018507:Gene Expression Regulation, Developmental; D018390:Gene Targeting; D018859:Hair Follicle / Q000033:anatomy & histology / Q000254:growth & development / Q000648:ultrastructure; D007150:Immunohistochemistry; D017403:In Situ Hybridization; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D008954:Models, Biological; D009024:Morphogenesis; D051880:Receptors, Notch; D012627:Sebaceous Glands / Q000002:abnormalities; D012867:Skin / Q000033:anatomy & histology / Q000254:growth & development*
D008565:Membrane Proteins; D051880:Receptors, Notch; D053829:Amyloid Precursor Protein Secretases; D010450:Endopeptidases; D016282:Aspartic Acid Endopeptidases; C509282:Bace1 protein, mouse