Loss of atm in Zebrafish as a Model of Ataxia–Telangiectasia Syndrome

Abstract

Ataxia–telangiectasia mutated (ATM) is a key DNA damage signaling kinase that is mutated in humans with ataxia–telangiectasia (A-T) syndrome. This syndrome is characterized by neurodegeneration, immune abnormality, cancer predisposition, and premature aging. To better understand the function of ATM in vivo, we engineered a viable zebrafish model with a mutated atm gene. Zebrafish atm loss-of-function mutants show characteristic features of A-T-like motor disturbance, including coordination disorders, immunodeficiency, and tumorigenesis. The immunological disorder of atm homozygote fish is linked to the developmental blockade of hematopoiesis, which occurs at the adulthood stage and results in a decrease in infection defense but, with little effect on wound healing. Malignant neoplasms found in atm mutant fish were mainly nerve sheath tumors and myeloid leukemia, which rarely occur in A-T patients or Atm−/− mice. These results underscore the importance of atm during immune cell development. This zebrafish A-T model opens up a pathway to an improved understanding of the molecular basis of tumorigenesis in A-T and the cellular role of atm.

atm Mutation and Oxidative Stress Enhance the Pre-Cancerous Effects of UHRF1 Overexpression in Zebrafish Livers

“…All adults were genotyped by sanger sequencing prior to use. Previous studies reported that atm zebrafish mutants were sterile [ 17 ]. We assessed fecundity and reproductive success of atm −/− by comparing mating success of five individual mating pairs of WT and atm −/− mated six times over a 2-month period ( Figure 3 A), by counting the number of embryos produced per successful mating ( Figure 3 B).…”

“…There are some additional questions raised by these studies that require further investigation. The allele reported here displays different phenotypes from an atm zebrafish mutant allele that was recently reported to have defects in germ cell development and movement [ 17 ]. It is possible that different genetic backgrounds or husbandry conditions could modify the penetrance of atm dependent phenotypes.…”

“…Homozygous ATM mutation underlies a human genetic disorder characterized by immune dysfunction, reproductive, mobility and neurological defects and, importantly, predisposition to cancer. These phenotypes are partially replicated in mouse and zebrafish models with Atm deficiency [ 15 , 16 , 17 ] and the non-cancer related phenotypes in these patients and experimental models have been attributed to functions of ATM that are unrelated to the DDR. This is supported by findings from patients with ATM mutations that affect kinase activity but leave other functions intact, and from experimental studies with ATM kinase inhibitors and kinase-dead mutants which show that these perturbations of ATM function are more potent in carcinogenesis than are null mutations [ 13 ].…”

“…Zebrafish are a widely used cancer model and the role of Tp53 and upstream signaling pathways in cancer related phenotypes have been studied widely in this model [ 35 , 36 , 37 , 38 , 39 ]. In one study, atm deficiency was shown to sensitize zebrafish embryos to ionizing radiation [ 40 ] and another showed that loss-of-function atm mutants results in germ cell and motility defects and increases the incidence of cancer in adult zebrafish [ 17 ], mimicking phenotypes displayed by mouse mutants [ 15 , 41 ] and some ATM patients. Other insight came from a study showing that radiosensitivity of zebrafish embryos and mammalian cells which have compromised DDR response due to a combination of tp53 mutation and Chk1 inhibition can be reversed by knocking down Atm [ 39 ].…”

Zebrafish: A Relevant Genetic Model for Human Primary Immunodeficiency (PID) Disorders?

“…Ataxia-telangiectasia (A-T) syndrome is a human disorder characterized by neurodegeneration, immune dysregulation, cancer susceptibility and premature aging and results from defects in the ATM gene [ 43 ]. Zebrafish LOF atm mutants exhibited similar phenotypes, with multi-lineage immunodeficiency along with motor disturbances and cancer predisposition [ 75 ]. Finally, human BCL11B gain-of-function (GOF) mutations have been identified in an autosomal-dominant syndrome characterized by reduced T cells, congenital craniofacial abnormalities and neurocognitive defects [ 76 ], with overexpression of a patient-derived BCL11B mutant in bcl11b KD zebrafish embryos able to model the T cell defects and dominant nature of the human disease [ 44 ].…”