NeuroD1 induces microglial apoptosis and cannot induce microglia-to-neuron cross-lineage reprogramming.

The regenerative capacity of neurons is limited in the central nervous system (CNS), with irreversible neuronal loss upon insult. In contrast, microglia exhibit extraordinary capacity for repopulation. Matsuda et al. (2019) recently reported NeuroD1-induced microglia-to-neuron conversion, aiming to provide an "unlimited" source to regenerate neurons. However, the extent to which NeuroD1 can exert cross-lineage reprogramming of microglia (myeloid lineage) to neurons (neuroectodermal lineage) is unclear. In this study, we unexpectedly found that NeuroD1 cannot convert microglia to neurons in mice. Instead, NeuroD1 expression induces microglial cell death. Moreover, lineage tracing reveals non-specific leakage of similar lentiviruses as previously used for microglia-to-neuron conversion, which confounds the microglia-to-neuron observation. In summary, we demonstrated that NeuroD1 cannot induce microglia-to-neuron cross-lineage reprogramming. We here propose rigid principles for verifying glia-to-neuron conversion. This Matters Arising paper is in response to Matsuda et al. (2019) , published in Neuron. [Display omitted] • Ectopic expression of NeuroD1 cannot induce microglia-to-neuron conversion in mice • Lentiviral leakage suggests labeling of cells other than microglia • Glia-to-neuron conversion by NeuroD1 should always be tested by rigid lineage tracing NeuroD1-induced cross-lineage microglia-to-neuron conversion is hotly debated. Rao et al. demonstrate that NeuroD1 does not induce microglia-to-neuron conversion in mice. Instead, NeuroD1 triggers microglial apoptosis. Rao et al. further propose generic principles for verifying glia-to-neuron conversion. [ABSTRACT FROM AUTHOR]