Epidermolysis bullosa and embryonic lethality in mice lacking the multi-PDZ domain protein GRIP1.
Glutamate receptor-interacting protein 1 (GRIP1) is an adaptor protein composed of seven PDZ (postsynaptic density-95/Discs large/zona occludens-1) domains, capable of mediating diverse protein-protein interactions. GRIP1 has been implicated in the regulation of neuronal synaptic function, but its physiologic roles have not been defined in vivo. We find that elimination of murine GRIP1 results in embryonic lethality. GRIP1(-/-) embryos develop abnormalities of the dermo-epidermal junction, resulting in extensive skin blistering around day 12 of embryonic life. Ultra-structural characterization of the blisters (or bullae) revealed cleavage of the dermo-epidermal junction below the lamina densa, an alteration reminiscent of the dystrophic form of human epidermolysis bullosa. Blisters were also observed in the lateral ventricle of the brain and in the meninges covering the cerebral cortex. These genetic data suggest that the GRIP1 scaffolding protein is required for the formation and integrity of the dermo-epidermal junction and reveal the importance of PDZ domains in the organization of supramolecular structures essential for mammalian embryonic development.
Bladt
Friedhelm
F
Programme in Molecular Biology and Cancer, Samuel Lunenfeld Research Institute, Mount Sinai Hospital, 600 University Avenue, Toronto, ON, Canada M5G 1X5.
Tafuri
Anna
A
Gelkop
Sigal
S
Langille
Lowell
L
Pawson
Tony
T
D000818:Animals; D002970:Cleavage Stage, Ovum; D004817:Epidermis / Q000196:embryology / Q000378:metabolism / Q000473:pathology; D016108:Epidermolysis Bullosa Dystrophica / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D005313:Fetal Death; D015870:Gene Expression; D018390:Gene Targeting; D006801:Humans; D008648:Mesoderm; D051379:Mice; D018345:Mice, Knockout; D009420:Nervous System / Q000196:embryology / Q000378:metabolism / Q000473:pathology; D051958:Nuclear Receptor Coactivator 2; D012867:Skin / Q000473:pathology; D014157:Transcription Factors / Q000235:genetics / Q000502:physiology*
C498001:NCOA2 protein, human; C498002:Ncoa2 protein, mouse; D051958:Nuclear Receptor Coactivator 2; D014157:Transcription Factors