Oral Presentation Hunter Cell Biology Meeting 2022

Temporal identity of dedifferentiation-induced neural stem cells (#61)

Louise Cheng 1 , Kellie Veen 1 , Qian Dong 1 , Edel Alvarez 1 , Phuong-Khanh Nguyen 1 , Owen Marshall 2 , Kieran Harvey 3 , Francesca Froldi 1 , Patricia Jusuf 4
  1. Growth regulation laboratory, Cancer research division, Peter MacCallum Cancer Centre, Melbourne , VIC, Australia
  2. Menzies Institute for Medical Research, Hobart, Australia
  3. Peter MacCallum Cancer Center, Harvey Lab, Melbourne, Victoria
  4. Bioscience, University of Melbourne, Melbourne, Vic, Australia

Dedifferentiation is the reversion of differentiated cells to a stem cell like fate. We have previously shown that during neurogenesis, a number of transcription factors are required in the neurons to maintain their differentiated status. Failure to maintain neuronal differentiation results in the formation of ectopic neuroblasts (NBs). However, it is not known whether dedifferentiated NBs can faithfully produce the sequence of unique neurons that populate the brain, normally dependent on the expression of temporal transcription factors (tTFs). Here, we show that the dedifferentiated NBs induced via the overexpression of bHLH transcription factor Deadpan (Dpn) in the medulla are unable to produce the correct types of neurons or undergo terminal differentiation. This is because these NBs are stalled in the cell cycle and are stuck in a Sloppy-paired 1 (Slp) positive temporal window. These middle-aged NBs fail to acquire the competence to produce neurons and glial cells normally made by older NBs or to undergo timely terminally differentiation. The stalling of the temporal progression can be re-initiated by two means, overexpression of Dichaete (D), a Sox-box transcription factor that can repress Slp; or via promoting G1-S cell cycle progression. Together our data shows that the competence of dedifferentiated NBs to produce the right number and types of neurons is dependent on their temporal identity and cell cycle progression.