Deficiency of suppressor enhancer Lin12 1 like (SEL1L) in mice leads to systemic endoplasmic reticulum stress and embryonic lethality.
Stress in the endoplasmic reticulum (ER) plays an important causal role in the pathogenesis of several chronic diseases such as Alzheimer, Parkinson, and diabetes mellitus. Insight into the genetic determinants responsible for ER homeostasis will greatly facilitate the development of therapeutic strategies for the treatment of these debilitating diseases. Suppressor enhancer Lin12 1 like (SEL1L) is an ER membrane protein and was thought to be involved in the quality control of secreted proteins. Here we show that the mice homozygous mutant for SEL1L were embryonic lethal. Electron microscopy studies revealed a severely dilated ER in the fetal liver of mutant embryos, indicative of alteration in ER homeostasis. Consistent with this, several ER stress responsive genes were significantly up-regulated in the mutant embryos. Mouse embryonic fibroblast cells deficient in SEL1L exhibited activated unfolded protein response at the basal state, impaired ER-associated protein degradation, and reduced protein secretion. Furthermore, markedly increased apoptosis was observed in the forebrain and dorsal root ganglions of mutant embryos. Taken together, our results demonstrate an essential role for SEL1L in protein quality control during mouse embryonic development.
Francisco
Adam B
AB
Department of Animal Science, College of Agriculture and Life Sciences, Cornell University, Ithaca, New York 14850, USA.
Singh
Rajni
R
Li
Shuai
S
Vani
Anish K
AK
Yang
Liu
L
Munroe
Robert J
RJ
Diaferia
Giuseppe
G
Cardano
Marina
M
Biunno
Ida
I
Qi
Ling
L
Schimenti
John C
JC
Long
Qiaoming
Q
D000544:Alzheimer Disease / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D000818:Animals; D003920:Diabetes Mellitus / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D020964:Embryo Loss / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D004622:Embryo, Mammalian / Q000378:metabolism* / Q000648:ultrastructure; D047108:Embryonic Development; D004721:Endoplasmic Reticulum / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D018507:Gene Expression Regulation, Developmental; D047908:Intracellular Signaling Peptides and Proteins; D051379:Mice; D008817:Mice, Mutant Strains; D010300:Parkinson Disease / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D011506:Proteins / Q000235:genetics / Q000378:metabolism*; D056811:Unfolded Protein Response
D047908:Intracellular Signaling Peptides and Proteins; D011506:Proteins; C492169:Sel1h protein, mouse