Histopathological and Neurological Features of Atg4b Knockout Mice

Abstract

This investigation found that genetic inactivation of mouse Atg4b, 1 of the 4 mammalian homologs of the autophagy-related gene Atg4, resulted in amorphous globular bodies in the neuropil of the deep cerebellar nuclei and adjacent vestibular nuclei but nowhere else in the brain or other tissues. The spheroid-like bodies in the deep cerebellar and vestibular nuclei showed heterogeneous composition, reactivity with anti-ubiquitin antibody, and staining characteristics of proteinaceous material. Atg4b-deficient (Atg4b -/-) mice also showed a mild but measurable impairment of motor performance on the Rotarod. Atg4b-/-mice produced by breeding heterozygous parents were produced at a slightly lower than expected ratio to heterozygous and wild-type siblings but showed no other clear abnormalities in a battery of screening tests. These findings appear to be different than those reported for inactivation of other Atg4 homologs, suggesting that these homologs have tissue-specific functions beyond redundancy.

ATG4B promotes colorectal cancer growth independent of autophagic flux

“…More interestingly, atg4b −/− mice only show a slight defect on otoconial development of the inner ear, without growth inhibition or other clear abnormalities. 19,54 Our data also showed that the growth rate of atg4b −/− 3T3 cells was similar to that of Atg4b +/+ 3T3 cells (Fig. S9), revealing that the regulation of ATG4B on cell proliferation in colorectal cancer cells might be different from normal cells due to the complicated nature of cancer.…”

The core autophagy protein ATG4B is a potential biomarker and therapeutic target in CML stem/progenitor cells

“…This interpretation is further supported by studies using mouse models lacking various ATG4 family members, where ATG4C knockout mice display a mild autophagy defect but ATG4B null mice display defective proteolytic cleavage of LC3 and demonstrate a systemic reduction in autophagic flux. 34,37,54 Even though ATG4A and ATG4D transcripts were detected, it is possible that these also play minor roles in the autophagic process in primitive CD34…”

“…31,32 Mammals express 4 different ATG4 paralogs (ATG4A, ATG4B, ATG4C, and ATG4D), with ATG4B being crucial for the autophagic process and having the broadest substrate spectrum for different LC3 forms and homologs. [33][34][35][36][37] Although autophagy is a well-studied process that takes place at basal levels in most mammalian cells, its roles in the regulation of hematopoiesis and pathogenesis of leukemia have yet to be fully explored. Recently, it was reported that autophagy can be induced upon IM treatment in CML cell lines and primary patient samples and that the process could be partially impaired by knockdown of ATG5 or ATG7.…”

AMBRA1-regulated autophagy in vertebrate development

“…Besides the post-fertilization steps described above, Atg3, Atg5, Atg7 and Atg16L1 genes appear not to be essential for embryogenesis, since their knockout embryos properly complete the development, but die postnatal, since autophagy plays an undisputed role for the survival of animals before breastfeeding care (Komatsu et al, 2005;Kuma et al, 2004;Saitoh et al, 2008;Saitoh and Fujita, 2009;Sou et al, 2008). Conversely, LC3, GABARAP, Atg4b and Atg4c mutant mice develop normally and also survive after birth, probably because of the presence of multiple Atg4 and LC3 paralogues in mammals (Cann et al, 2008;Mariño et al, 2010;O'Sullivan et al, 2005;Read et al, 2011). It was also described that Atg5/ Atg7 deleted mice form autophagosomes and amphisomes without LC3 lipidation; this Atg5-independent autophagy was detected in several embryonic tissues, playing a relevant role in clearing mitochondria during erythroid maturation (Nishida et al, 2009).…”