A Myt1 family transcription factor defines neuronal fate by repressing non-neuronal genes

Abstract

Cellular differentiation requires both activation of target cell transcriptional programs and repression of non-target cell programs. The Myt1 family of zinc finger transcription factors contributes to fibroblast to neuron reprogramming in vitro. Here, we show that ztf-11 ( Zinc-finger Transcription Factor-11), the sole Caenorhabditis elegans Myt1 homolog, is required for neurogenesis in multiple neuronal lineages from previously differentiated epithelial cells, including a neuron generated by a developmental epithelial-to-neuronal transdifferentiation event. ztf-11 is exclusively expressed in all neuronal precursors with remarkable specificity at single-cell resolution. Loss of ztf-11 leads to upregulation of non-neuronal genes and reduced neurogenesis. Ectopic expression of ztf-11 in epidermal lineages is sufficient to produce additional neurons. ZTF-11 functions together with the MuvB corepressor complex to suppress the activation of non-neuronal genes in neurons. These results dovetail with the ability of Myt1l (Myt1-like) to drive neuronal transdifferentiation in vitro in vertebrate systems. Together, we identified an evolutionarily conserved mechanism to specify neuronal cell fate by repressing non-neuronal genes.

eLife digest

The human body contains many cell types that each have different job and can look very different from each other. However, each of the cells in an individual’s body contains almost exactly the same genes, because all of them share the same DNA inherited from the individual’s parents. Cells therefore become different from one another by controlling the activity of sets of genes. They do this by using proteins called transcription factors, which find specific genes and turn them either on or off.

Nerve cells or neurons form and develop in a process called neurogenesis. During neurogenesis, some genes including those specific to neurons need to be switched on while other non-neuronal genes need to be switched off. The “off-switch” is particularly important when neurons are generated by conversion from skin cells, which sometimes happens in animals. Before these cells can become mature nerve cells, they require transcription factors to ensure that skin-specific genes are off.

The transcription factors turning on nerve cell-specific genes are well-understood, but far less is known about those that turn off other genes. Lee et al. therefore set out to search for transcription factors that might switch off non-neuronal genes during neurogenesis and focused on one transcription factor that is known to be important for the development of nerve cells in a variety of animal species.

Experiments using the worm C. elegans revealed that this transcription factor – called ZTF-11 in worms – was present in all cells destined to be nerve cells, but not in cells that would assume other roles. These experiments are possible with C. elegans because the final role, or ‘fate’, of each cell in the body are already known, all the way from the fertilized egg to the adult.

Further work, using genetically engineered worms revealed that ZTF-11 worked by turning off genes that are related to the development of non-nerve cells. Deleting the gene for ZTF-11 in immature nerve cells allowed these cells to turn on different sets of genes and resulted in adult worms with fewer mature nerve cells than normal worms. On the other hand, forcing other cell types (which would not normally become part of the nervous system) to produce ZTF-11 was sufficient to convert them into nerve cells.

These results are an important step forward in understanding how nerve cells are built in the developing body, especially how nerve cells can be made from other cell types. In the future, this knowledge could be used to help people with diseases of the nervous system, such as Parkinson’s disease.