MACF1, versatility in tissue-specific function and in human disease

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Abstract

Spectraplakins are a family of evolutionarily conserved gigantic proteins and play critical roles in many cytoskeleton-related processes. Microtubule actin crosslinking factor 1 (MACF1) is one of the most versatile spectraplakin with multiple isoforms. As a broadly expressed mammalian spectraplakin, MACF1 is important in maintaining normal functions of many tissues. The loss-of-function studies using knockout mouse models reveal the pivotal roles of MACF1 in embryo development, skin integrity maintenance, neural development, bone formation, and colonic paracellular permeability. Mutation in the human MACF1 gene causes a novel myopathy genetic disease. In addition, abnormal expression of MACF1 is associated with schizophrenia, Parkinson’s disease, cancer and osteoporosis. This demonstrates the crucial roles of MACF1 in physiology and pathology. Here, we review the research advances of MACF1’s roles in specific tissue and in human diseases, providing the perspectives of MACF1 for future studies.

Section snippets

MACF1: a versatile spectraplakin

Microtubule actin crosslinking factor 1 (MACF1), also known as actin crosslinking factor 7 (ACF7), MACF, macrophin [1], and trabeculin-α [2], was firstly identified by screening for additional members of the actin crosslinker superfamily [3]. MACF1 is encoded by the MACF1 gene that is located on the human chromosome 1p32 and the mouse chromosome 4 [4], [5]. Gong and colleagues have identified that the human MACF1 gene comprises at least 102 exons and spans over 270 kb [4]. The MACF1 gene is a

MACF1’s functions in specific tissue

The ubiquitous expression pattern of MACF1 in both embryo and adult tissues demonstrates its important and extensive roles. To get better understanding of the physiological and pathological roles of MACF1, researchers conduct the loss-of-function studies by generating MACF1 knockout mouse models in different tissues or cells (Table 1).

MACF1 and human genetic diseases

The first instance of MACF1-related human genetic disease was reported in one family in 2014 [24]. It is a novel myopathy named as “spectraplakinopathy type I” according to that MACF1 is a member of spectraplakin family. The “spectraplakinopathy type I” is characterized by periodic hypotonia, lax muscles and diminished motor skills [24]. The genetic analysis showed that there was a duplication of the MACF1 gene on the chromosome 1p34.3, leading to overall decrease of MACF1 levels. The reduction

Conclusions and perspectives

Here we reviewed the recent findings of MACF1’s physiological and pathological roles uncovered by studies from both animal models and human diseases. Given the ubiquitously expressed pattern and multifunctional characteristics, it is not surprising that standard knockout of MACF1 results in embryonic lethality. Besides the necessity of MACF1 for embryo development, tissue-specific knockout of MACF1 reveals its critical physiological functions in skin integrity maintenance, neurodevelopment,

Acknowledgements

This work was supported by the National Natural Science Foundation of China (grant numbers 31400725, 31570940), the Project Funded by China Postdoctoral Science Foundation (grant number 2015T81051, 2017M610653), Young Talent Fund of University Association for Science and Technology in Shaanxi, China (20170401), the Fundamental Research Funds for the Central Universities (grant number 3102016ZY037), and the Shenzhen Science and Technology Project (grant number JCYJ20160229174320053).

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