Functional Study Of Zinc Finger Protein Zfpm Family In Zebrafish Heart Development

The heart is the first organ to form and play a notable role during vertebrate embryogenesis.Heart disease is one of the most life-threatening disease which cause human death and is associated with extremely high rates of morbidity and mortality.Among them,congenital heart disease(CHD)is related to the abnormal transcription of cardiac genes.Left Ventricular Non-compaction(LVCN)is one of the inherited form myocardiopathies.It is generally believed that LVCN caused an abnormal increase in myocardial trabecula due to failure of hereditary factors in the embryonic development stage,leading to a severe myocardial disease.Although the cause of LVNC has been extensively studied,the mechanism is still not clear.Zinc finger transcription factor GATA family plays an important role in regulating the development of vertebrate heart,blood cells and other tissues and organs.It was found that the Zinc finger protein ZFPM family(also known as FOG)were identified as factors that only bind to GATA transcription factors and regulates downstream gene expression through multiple modes.ZFPM recruits nucleosome remodeling and deacetylase complex(NuRD)to its N-terminus and C terminal binding protein(CtBP),mediating the transcription of GATA transcriptional factor to maintain the normal development of multiple tissues and organs in vertebrates.This study adopt zebrafish as a model animal,based on its high homology with human genome,the molecular pathways involved in embryonic development are evolutionarily conserved,and with biological characteristics such as small size,easy breeding and feeding,short growth cycle,and external fertilized embryos.Zebrafish is suitable for gene editing and early embryonic development studies.The ZFPM family has three genes in zebrafish:zfpm1,zfpm2a and zfpm2b.We generated the zfpm1,zfpm2a and zfpm2b mutants by CRISPR/Cas9 and gene trapping technology for studying the biological function of Zfpm family in zebrafish development.We found that in zebrafish zfpm1-/-juvenile,cardiac function is significantly compromised,with hearts exhibiting deformed trabecular meshwork.To elucidate the mechanisms of Zfmpl function in cardiac trabeculation,we analyzed zfm1 mutant hearts more closely and found that loss of Zfmp1 activity resulted in over-activation of Neuregulin-ErbB signaling and abnormally elevated cardiomyocyte proliferation during cardiac trabeculae growth and modeling stages.Knockout of zfpm2a and zfpm2b respectively did not affect the development of zebrafish heart and maturation,while zfpm2a,zfpm2b double mutation fish showed evident growth retardant,while the ventrile trabeculation was not affected.These results implicate Zfinp1 plays a pivotal role in coordinating trabeculae patterning and growth.