Content of review 1, reviewed on May 14, 2024
Kalyn et al., present a comprehensive study into the role of Nr4a2, known to be a key driver of dopaminergic neural fates. A strength of the study lies in analysing the mutant phenotype across many different layers including neuroanatomy, gene expression, metabolic and mitochondrial function and role in regeneration.
Overall, nicely written, comprehensive model and the figures clearly demonstrate the key results. The discussion is well written and encompassing.
One key aspect that should in the very least be discussed more is the relatively mild phenotype in the homozygous mutants of both 2a and 2b. I appreciate that the genome duplication and two paralogues with divergent function would explain why the phenotype is not as severe as for example the mouse. However, the loss of th1 transcript and number of dat:GFP cells in neither mutant is very large, which seems at odds with either of those paralogues being crucial for dopaminergic neurogenesis.
I think it would be fairly straight forward and very informative to cross the double mutants and assess at just one early time point, whether complete loss of dat:GFP or th1 occured or if double mutants are not viable.
Additionally, expression of each paralogue in the KO of the other, would be very informative to assess the level of potential functional compensation. It would also be interesting (but outside the scope of the current study) to assess whether one paralogue is upregulated in anatomical regions in which it is not normally expressed to rescue function within that region.
Out of scientific interest, but again outside the scope of the current study, it would be interesting in future to assess how the regeneration after MPTP exposure might differe in 2a or 2b homozygous mutants.
Minor comments:
Page 6, line 10 – delete extra comma.
Page 10 line 15 – is missing a closing bracket “)” sign.
Page 22 line 55 needs a space after “1997)”.
Page 23 line 36 needs a full stop.
Page 23 line 38 has an extra comma that needs to be deleted.
Source
© 2024 the Reviewer.
Content of review 2, reviewed on August 12, 2024
The authors' have addressed my questions, congratulations on this manuscript.
Source
© 2024 the Reviewer.
References
Michael, K., Rose, G., Hyojin, L., Aishi, M. H., Jory, C., Vishal, S., A., M. J., Marc, E. 2024. Differential roles of NR4A2 (NURR1) paralogs in the brain and behavior of zebrafish. Journal of Neurochemistry.
