The transcription factor Nerfin-1 prevents reversion of neurons into neural stem cells

Abstract

Cellular dedifferentiation is the regression of a cell from a specialized state to a more multipotent state and is implicated in cancer. However, the transcriptional network that prevents differentiated cells from reacquiring stem cell fate is so far unclear. Neuroblasts (NBs), the Drosophila neural stem cells, are a model for the regulation of stem cell self-renewal and differentiation. Here we show that the Drosophila zinc finger transcription factor Nervous fingers 1 (Nerfin-1) locks neurons into differentiation, preventing their reversion into NBs. Following Prospero-dependent neuronal specification in the ganglion mother cell (GMC), a Nerfin-1-specific transcriptional program maintains differentiation in the post-mitotic neurons. The loss of Nerfin-1 causes reversion to multipotency and results in tumors in several neural lineages. Both the onset and rate of neuronal dedifferentiation in nerfin-1 mutant lineages are dependent on Myc-and target of rapamycin (Tor)-mediated cellular growth. In addition, Nerfin-1 is required for NB differentiation at the end of neurogenesis. RNA sequencing (RNA-seq) and chromatin immunoprecipitation (ChIP) analysis show that Nerfin-1 administers its function by repression of selfrenewing-specific and activation of differentiation-specific genes. Our findings support the model of bidirectional interconvertibility between neural stem cells and their post-mitotic progeny and highlight the importance of the Nerfin-1-regulated transcriptional program in neuronal maintenance.

Prevention of medulla neuron dedifferentiation by Nerfin-1 requires inhibition of Notch activity

“…On the other hand, absence of Lola leads to neuron-to-NB reversion and tumorigenesis (Southall et al, 2014), but it is crucial for neuronal maintenance only in the optic lobe. Recently, a paper reported that Nerfin-1 loss induces neuron dedifferentiation in both central brain and VNC (Froldi et al, 2015). In the present study, we demonstrate a conserved function for Nerfin-1 in medulla neurons in the optic lobe.…”

“…A recent study suggests that Nerfin-1 maintains neuron differentiation in both central brains and VNCs (Froldi et al, 2015). In that study, Myc and Target of rapamycin (Tor) were reported to be necessary for the dedifferentiation caused by Nerfin-1 loss.…”

Histidine is selectively required for the growth of Myc‐dependent dedifferentiation tumours in the Drosophila CNS

“…Histidine deprivation inhibits the growth of nerfin-1 but not pros clones or wildtype stem cells Mutations in the zinc finger transcription factor Nerfin-1, which is predominantly expressed in postmitotic neural lineages, provide a useful model for neural dedifferentiation-derived clones in the CNS (Froldi et al, 2015;Xu et al, 2017). In nerfin-1 mutant clones, neurons switch off the expression of differentiation genes in favour of stem cell markers, resulting in tumour-like lineages which exhibit unlimited proliferative potential, that fail to differentiate and are metastatic when transplanted into naive adult hosts (Froldi et al, 2015 and Fig 1A).…”

“…In pros clones, however, the NB diameter and nucleolar/nuclear ratio were not significantly affected by histidine dietary withdrawal (Fig 3H, K and L). Furthermore, unlike nerfin-1 NBs which exhibit~3-fold increase in nucleolus/nuclear volume ratio compared to control (Froldi et al, 2015), pros NBs are not significantly different from control NBs in terms of cellular growth ( Fig 4D). This is primarily because pros NB-like cells tend to be much smaller than their wildtype counterparts (Fig 4A-C).…”

“…Similarly, a 75% decrease in dietary histidine during larval development also led to a significant increase in the proportion of Elav + neurons with a corresponding decrease in the proportion of Mira + NBs (Fig 3F and G). Unlike wildtype neurons, a rapid increase in cellular growth reflected by increased ribosome biogenesis is a prerequisite for nerfin-1 neuron-to-neuroblast dedifferentiation (Froldi et al, 2015). Unlike wildtype neurons, a rapid increase in cellular growth reflected by increased ribosome biogenesis is a prerequisite for nerfin-1 neuron-to-neuroblast dedifferentiation (Froldi et al, 2015).…”