Selective role of the DNA helicase Mcm5 in BMP retrograde signaling during Drosophila neuronal differentiation

Abstract

The MCM2-7 complex is a highly conserved hetero-hexameric protein complex, critical for DNA unwinding at the replicative fork during DNA replication. Overexpression or mutation in MCM2-7 genes is linked to and may drive several cancer types in humans. In mice, mutations in MCM2-7 genes result in growth retardation and mortality. All six MCM2-7 genes are also expressed in the developing mouse CNS, but their role in the CNS is not clear. Here, we use the central nervous system (CNS) of Drosophila melanogaster to begin addressing the role of the MCM complex during development, focusing on the specification of a well-studied neuropeptide expressing neuron: the Tv4/FMRFa neuron. In a search for genes involved in the specification of the Tv4/FMRFa neuron we identified Mcm5 and find that it plays a highly specific role in the specification of the Tv4/FMRFa neuron. We find that other components of the MCM2-7 complex phenocopies Mcm5, indicating that the role of Mcm5 in neuronal subtype specification involves the MCM2-7 complex. Surprisingly, we find no evidence of reduced progenitor proliferation, and instead find that Mcm5 is required for the expression of the type I BMP receptor Tkv, which is critical for the FMRFa expression. These results suggest that the MCM2-7 complex may play roles during CNS development outside of its well-established role during DNA replication. The MCM2-7 complex plays a critical role in the DNA replication allowing cells to progress throughout the cell cycle and divide. Overexpression or mutation in MCM2-7 genes is linked to and may drive several cancer types in humans. While MCM2-7 complex is widely expressed in the central nervous system (CNS) during development, its role is not yet clear. Here, we use the CNS of Drosophila melanogaster to address the role of the MCM complex, focusing on the specification of a well-studied neuropeptide expressing neuron: the Tv4/FMRFa neuron. We identified that Mcm5 plays a highly specific role in the specification of this neuron, and it involves other components of the MCM2-7 complex. Despite the described importance of this complex on DNA replication, we find no evidence of reduced progenitor proliferation, and instead we find that Mcm5 is required for the expression of the type I BMP receptor Tkv, which is critical for the specification of the Tv4/FMRFa neuron. These results suggest that the MCM2-7 complex may play roles during CNS development outside of its well-established role during DNA replication.