Abstract
Neuronal differentiation is exquisitely controlled both spatially and temporally during nervous system development. Defects
in the spatiotemporal control of neurogenesis cause incorrect formation of neural networks and lead to neurological
disorders such as epilepsy and autism. The mTOR kinase integrates signals from mitogens, nutrients and energy levels to
regulate growth, autophagy and metabolism. We previously identified the insulin receptor (InR)/mTOR pathway as a critical
regulator of the timing of neuronal differentiation in the Drosophila melanogaster eye. Subsequently, this pathway has been
shown to play a conserved role in regulating neurogenesis in vertebrates. However, the factors that mediate the neurogenic
role of this pathway are completely unknown. To identify downstream effectors of the InR/mTOR pathway we screened
transcriptional targets of mTOR for neuronal differentiation phenotypes in photoreceptor neurons. We identified the
conserved gene unkempt (unk), which encodes a zinc finger/RING domain containing protein, as a negative regulator of the
timing of photoreceptor differentiation. Loss of unk phenocopies InR/mTOR pathway activation and unk acts downstream of
this pathway to regulate neurogenesis. In contrast to InR/mTOR signalling, unk does not regulate growth. unk therefore
uncouples the role of the InR/mTOR pathway in neurogenesis from its role in growth control. We also identified the gene
headcase (hdc) as a second downstream regulator of the InR/mTOR pathway controlling the timing of neurogenesis. Unk
forms a complex with Hdc, and Hdc expression is regulated by unk and InR/mTOR signalling. Co-overexpression of unk and
hdc completely suppresses the precocious neuronal differentiation phenotype caused by loss of Tsc1. Thus, Unk and Hdc are
the first neurogenic components of the InR/mTOR pathway to be identified. Finally, we show that Unkempt-like is expressed
in the developing mouse retina and in neural stem/progenitor cells, suggesting that the role of Unk in neurogenesis may be
conserved in mammals.
in the spatiotemporal control of neurogenesis cause incorrect formation of neural networks and lead to neurological
disorders such as epilepsy and autism. The mTOR kinase integrates signals from mitogens, nutrients and energy levels to
regulate growth, autophagy and metabolism. We previously identified the insulin receptor (InR)/mTOR pathway as a critical
regulator of the timing of neuronal differentiation in the Drosophila melanogaster eye. Subsequently, this pathway has been
shown to play a conserved role in regulating neurogenesis in vertebrates. However, the factors that mediate the neurogenic
role of this pathway are completely unknown. To identify downstream effectors of the InR/mTOR pathway we screened
transcriptional targets of mTOR for neuronal differentiation phenotypes in photoreceptor neurons. We identified the
conserved gene unkempt (unk), which encodes a zinc finger/RING domain containing protein, as a negative regulator of the
timing of photoreceptor differentiation. Loss of unk phenocopies InR/mTOR pathway activation and unk acts downstream of
this pathway to regulate neurogenesis. In contrast to InR/mTOR signalling, unk does not regulate growth. unk therefore
uncouples the role of the InR/mTOR pathway in neurogenesis from its role in growth control. We also identified the gene
headcase (hdc) as a second downstream regulator of the InR/mTOR pathway controlling the timing of neurogenesis. Unk
forms a complex with Hdc, and Hdc expression is regulated by unk and InR/mTOR signalling. Co-overexpression of unk and
hdc completely suppresses the precocious neuronal differentiation phenotype caused by loss of Tsc1. Thus, Unk and Hdc are
the first neurogenic components of the InR/mTOR pathway to be identified. Finally, we show that Unkempt-like is expressed
in the developing mouse retina and in neural stem/progenitor cells, suggesting that the role of Unk in neurogenesis may be
conserved in mammals.
| Original language | English |
|---|---|
| Article number | e1004624 |
| Pages (from-to) | 1-14 |
| Journal | PLoS Genetics |
| Volume | 10 |
| Issue number | 9 |
| Early online date | 11 Sept 2014 |
| DOIs | |
| Publication status | Published - 2014 |