MRC National Institute for Medical Research, London
Science for Health
Novel mechanism for the onset of neuronal cell differentiation
15 January 2010
During nervous system development, there is strict control of the differentiation of progenitor cells to form neurons. In part, this control is achieved by widespread inhibitory mechanisms that maintain progenitors and limit the upregulation of proneural genes that initiates neuronal differentiation. This raises the question of how such inhibition is overcome to enable the onset of differentiation.
A novel mechanism that removes inhibition and is essential for primary neuronal differentation has been uncovered in studies by Dorothy Sobieszczuk, Alexei Poliakov, Qiling Xu and David Wilkinson (pictured) in NIMR's Division of Developmental Neurobiology. They show that the proneural gene, neurogenin1, upregulates expression of Btbd6, which in turn is required for upregulation of neurogenin1. Btbd6 is as an adaptor protein that binds to and targets degradation of a transcriptional repressor protein, Plzf. They find that Plzf is widely expressed in neural progenitors and inhibits neuronal differentiation. The onset of neurogenesis thus requires a positive feedback loop in which upregulation of Btbd6 targets the degradation of an inhibitor, and this may underlie a discrete switch from a progenitor to differentiation state.
Elucidation of how the transition of neural progenitors to neuronal differentiation is regulated is of fundamental importance and potentially relevant to stem cell biology. Our finding that Plzf inhibits neurogenesis may have wider significance, as Plzf has previously been implicated in maintainence of progenitor cells during spermatogenesis and in myeloid differentiation. The latter role underlies the involvement of abnormal forms of Plzf protein in myeloid leukaemia. It will therefore be very interesting to understand more about how Btbd6a and Plzf regulate the transition of progenitors to differentiation, and whether analogous mechanisms involving targeted degradation regulate cell differentiation in other tissues.
David Wilkinson
Cells expressing Btbd6a
In cells expressing the adaptor protein Btbd6a (red signal), there is export of the transcriptional repressor Plzf (green signal) from the nucleus (blue signal).
Original article
The research findings are published in full in:
Dorothy F. Sobieszczuk, Alexei Poliakov, Qiling Xu, and David G. Wilkinson (2010)
A feedback loop mediated by degradation of an inhibitor is required to initiate neuronal differentiation
Genes and Development. Publisher abstract
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