Phenotypes Associated with This Genotype

Genotype
MGI:5827897

• Allelic Composition: Bloc1s1^{tm1a(EUCOMM)Hmgu}/Bloc1s1^{tm1a(EUCOMM)Hmgu}
• Genetic Background: C57BL/6N-A^tm1Brd Bloc1s1^{tm1a(EUCOMM)Hmgu}/Ics
• Cell Lines: HEPD0550_3_B11

• ♀: phenotype observed in females
• ♂: phenotype observed in males
• N: normal phenotype

mortality/aging

embryonic lethality, complete penetrance ( J:213033 )

• no viable mice are produced; homozygoys embryos fail to develop beyond ~E12.5

cellular

abnormal autophagy ( J:213033 )

• mouse embryonic fibroblasts (MEFs) derived from ~E11.5 embryos show a vastly increased number of autophagosomes relative to wild-type MEFs

• LC3 mRNA levels and cellular levels of the active lipidated protein form (LC3-II) are significantly higher than those in wild-type MEFs

abnormal mitophagy ( J:213033 )

• MEFs show a significant increase in the transcript and protein levels of TFEB (transcription factor EB, a master regulator of autophagic and lysosomal pathways) and its downstream targets (LAMP1 and p62), indicating an increased TFEB-mediated mitophagy rate

• however, TFEB, p62, LAMP1, and LC3-II proteins are localized in the correct cellular compartment

abnormal mitochondrial physiology ( J:213033 )

• MEFs are deficient in their maximal uncoupled respiration rate, reserve capacity and use of oxygen for ATP synthesis

• mitochondrial energetic defects are counterbalanced by increased glycolysis, both at baseline and following stimulation with glucose

• MEFs show a significant induction in the expression of several mitochondrial biogenesis genes, especially Ppargc1a (PGC-1alpha), to counteract the increased TFEB-mediated mitophagy rate, resulting in an increased mitochondrial turnover rate

• however, mitochondrial protein levels, mtDNA copy number and mitochondrial volume remain normal

homeostasis/metabolism

abnormal autophagy ( J:213033 )

• mouse embryonic fibroblasts (MEFs) derived from ~E11.5 embryos show a vastly increased number of autophagosomes relative to wild-type MEFs

• LC3 mRNA levels and cellular levels of the active lipidated protein form (LC3-II) are significantly higher than those in wild-type MEFs

abnormal mitophagy ( J:213033 )

• MEFs show a significant increase in the transcript and protein levels of TFEB (transcription factor EB, a master regulator of autophagic and lysosomal pathways) and its downstream targets (LAMP1 and p62), indicating an increased TFEB-mediated mitophagy rate

• however, TFEB, p62, LAMP1, and LC3-II proteins are localized in the correct cellular compartment