A Family of Laminin α2 Chain-Deficient Mouse Mutants: Advancing the Research on LAMA2-CMD

Abstract

The research on laminin α2 chain-deficient congenital muscular dystrophy (LAMA2-CMD) advanced rapidly in the last few decades, largely due to availability of good mouse models for the disease and a strong interest in preclinical studies from scientists all over the world. These mouse models continue to provide a solid platform for understanding the LAMA2-CMD pathology. In addition, they enable researchers to test laborious, necessary routines, but also the most creative scientific approaches in order to design therapy for this devastating disorder. In this review we present animals belonging to the laminin α2 chain-deficient "dy/dy" mouse family (dy/dy, dy 2J /dy 2J , dy 3K /dy 3K , dy W /dy W , et al.) and a summary of the scientific progress they facilitated. We also raise a few questions that need to be addressed in order to maximize the usefulness of laminin α2 murine mutants and to further advance the LAMA2-CMD studies. We believe that research opportunities offered by the mouse models for LAMA2-CMD will continuously support our efforts to find a treatment for the disease.

Multiple functions of autophagy in vascular calcification

“…Their result approved that Osteocytic EphrinB2 could limits autophagy through RhoA, which could be responsible for limiting mineral accumulation and carbonate substitution within the bioapatite matrix and restraining collagen fiber compaction [ 79 ]. Subsequently, further investigations unveiled that EphrinB2 deficiency in bones dysregulated many genes including Fam134b [ 80 ], Fbxo32 [ 81 ], Lama2 [ 82 ], Bnip3 [ 83 ], Peg3 [ 84 ], Eps8l1 [ 85 ], Klf1 [ 86 ], Tspo2 [ 87 ], and Unc5a [ 88 ], which is specifically related to a series of autophagy processes, including mitophagy and ER-phagy.…”

“…When FGFR4 and JNK-dependent activation, the autophagy initiated complex VPS34 and beclin-1 [90]. Therefore, on compression on how autophagy regulating VC, further investigations can plagiarize the above information from bone formation [80][81][82][83][84][85][86][87][88].…”

Brain Dysfunction in LAMA2-Related Congenital Muscular Dystrophy: Lessons From Human Case Reports and Mouse Models

“…Several mouse models of MDC1A exist, with distinct Lama2 expression properties and phenotypes ( Table 2 ; reviewed in this issue; Gawlik and Durbeej, 2020 ). dy/dy mice have a spontaneous mutation in a non-coding region of the Lama2 gene that results in substantially reduced laminin-α2 levels, causing muscular dystrophy, nervous system involvement, and premature death (Michelson et al, 1955 ).…”

“…This loss-of-function is best understood in skeletal muscle, where Lm-211, via interactions with dystroglycan and α7β1 integrin receptors, is critical for proper BM assembly and function, which in turn is needed for the stability of the muscle sarcolemma (Yurchenco et al, 2018). While muscle pathology is described in detail in other reviews of this issue (Accorsi et al, 2020;Barraza-Flores et al, 2020;Gawlik and Durbeej, 2020), in general these abnormalities include apoptosis, fibrosis, inflammation. However laminin-α2 deficiency in muscle also leads to an upregulation of Lm-411 (α4, β1, γ1;Patton et al, 1997), and Lm-511 (α5, β1, γ1), which normally disappear postnatally, remaining only at the neuromuscular junction (NMJ) in healthy adult muscle (Patton et al, 1997;Kölbel et al, 2019).…”

Zebrafish Models of LAMA2-Related Congenital Muscular Dystrophy (MDC1A)

“…The integration of observations in caf mutants with other in vivo models of LAMA2-MD should greatly aid in their translatability. In particular, several mutant mouse models accurately phenocopy key aspects of the human disease (Gawlik and Durbeej, 2020 ), and provide an opportunity to test and validate findings from the caf mutants and to determine their relevance to non-muscle systems. This is particularly true concerning therapy development, where a pipeline of large scale drug screening in zebrafish combined with testing and validation in the mouse may yield candidate therapeutics with the highest potential for successful translation to patients.…”