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Functional assessment of the “two-hit” model for neurodevelopmental defects in Drosophila and X. laevis models of 16p12.1 deletion

ABSTRACT: We recently identified a deletion on chromosome 16p12.1 that is mostly inherited and associated with multiple neurodevelopmental phenotypes, where severely affected probands carried an excess of rare pathogenic variants in the genome compared to mildly affected carrier parents. We hypothesized that the 16p12.1 deletion sensitizes the genome for disease, but other hits in the genetic background modulate the ultimate phenotypic trajectory. To test this model, we examined the individual contribution of 16p12.1 homologs towards neurodevelopmental, cellular and molecular phenotypes in Drosophila melanogaster and Xenopus laevis. We observed that 16p12.1 homologs affect multiple phenotypic domains, leading to developmental delay, seizure susceptibility, brain size alterations, abnormal neuronal morphology, and cellular proliferation defects. In contrast to genes within CNVs of higher de novo occurrence, such as 16p11.2 deletion, homologs of 16p12.1 genes did not interact with each other, were less connected in a human brain network, and were sensitive to variation in the genetic background. Moreover, 214 “two-hit” models in the fly eye identified additive (47%), suppressive (34.5%), and epistatic (18.5%) interactions between 16p12.1 homologs and 80 homologs of genes carrying “second-hits” in children with the deletion and genes within related neurodevelopmental pathways. In fact, homologs of the intellectual disability-associated “second-hit” gene SETD5 synergistically interacted with homologs of MOSMO, modifying brain and cellular phenotypes and leading to new neuronal defects. Our results provide functional evidence for the “two-hit” model of neurodevelopmental disorders, where multiple 16p12.1 genes sensitize the genome to developmental defects, and complex domain-specific interactions with “second-hit” genes define the final phenotypic manifestation.

ORGANISM(S): Drosophila melanogaster

PROVIDER: GSE151330 | GEO | 2020/05/28

REPOSITORIES: GEO

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Project description:ETV6-RUNX1 is associated with childhood B-cell acute lymphoblastic leukemia (B-ALL), but the consequence of ETV6-RUNX1 expression on cell lineage decision during B-cell leukemogenesis remains largely evasive. Clinically silent ETV6-RUNX1 preleukemic clones are frequently found in neonatal cord blood, but only a few carriers develop B-ALL as a result of the acquisition of secondary postnatal genetic hits, like KDM5C or PAX5 loss. However, understanding the mechanism involved in this transformation would advance the development of non-toxic prophylactic interventions to preleukemic carriers. Using genetic lineage tracing, we have examined the capacity of ETV6-RUNX1 in instructing a B-cell malignant phenotype. Restricted Cre-mediated activation of ETV6-RUNX1 from the endogenous Etv6 locus into B-cell precursors does not trigger B-ALL development. Similarly, concomitant transient ETV6-RUNX1 expression in hematopoietic progenitors close to restricted Cre-mediated introduction of second hit (Kdm5c loss) in B-cells fail to induce B-ALL. In contrast, targeting ETV6-RUNX1 in hematopoietic progenitors was required to induce leukemia. These mice develop either T-ALL or B-ALL, suggesting that the nature of the second hit may define tumor cell identity during ETV6-RUNX1 leukemogenesis. In order to uncover a potential exclusive effect of the second hit in establishing the leukemic phenotype, we next showed that the introduction of the second hit, either Kdm5c or Pax5 loss, to the ETV6-RUNX1 preleukemic clone confers the tumor B-cell identity without need of environmental infection exposure. The resulting B-ALLs clustered according to the second-hit by RNA sequencing (RNA-Seq) analysis. Together these results provide a novel paradigm for the generation of tumor B cells through ETV6-RUNX1 in vivo where the second hit confers the tumor cell-identity to the ETV6-RUNX1 preleukemic clone. These findings could be relevant to develop new therapeutic approaches to prevent disease development.

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Functional assessment of the “two-hit” model for neurodevelopmental defects in Drosophila and X. laevis models of 16p12.1 deletion

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