Notch signaling regulates Akap12 expression and primary cilia length during renal tubule morphogenesis
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This Zenodo record is a permanently preserved version of a PREreview. You can view the complete PREreview at https://prereview.org/reviews/7041742.
The paper explores some interesting concepts highlighting the role of Notch signalling in neural tube formation and its implications in neural disorders like Alagille Syndrome. We learn that Notch signalling is seminal in regulating neural tube morphogenesis even after S-shaped body formation. Disturbance in Notch signalling led to renal cysts of both cortical and medullary origin with gross morphological defects in post-natal mice kidneys.
Notch signalling is also crucial in renal epithelial cell division as demonstrated by defects in spheroid formation in collagen matrices. The key discovery of this study shows the importance of Notch signalling in maintaining ciliary length and …
This Zenodo record is a permanently preserved version of a PREreview. You can view the complete PREreview at https://prereview.org/reviews/7041742.
The paper explores some interesting concepts highlighting the role of Notch signalling in neural tube formation and its implications in neural disorders like Alagille Syndrome. We learn that Notch signalling is seminal in regulating neural tube morphogenesis even after S-shaped body formation. Disturbance in Notch signalling led to renal cysts of both cortical and medullary origin with gross morphological defects in post-natal mice kidneys.
Notch signalling is also crucial in renal epithelial cell division as demonstrated by defects in spheroid formation in collagen matrices. The key discovery of this study shows the importance of Notch signalling in maintaining ciliary length and microtubule arrangements. Inhibition of Notch pathway leads to longer cilia with abnormal 6/8+1 microtubule arrangement, highlighting the critical role of Notch signalling in cilia maintenance and potential ciliopathies.
Lastly, they introduced the possibility of Notch pathway in regulating Akap12 expression. Akap12 is responsible for recruiting centriole-associated proteins, which allow symmetric cell division. Thus, Notch's regulation of Akap12 levels could be associated with the cystic phenotype and defective spheroid formation described earlier.
CONCERNS/COMMENTS ABOUT THE STUDY:
One big concern is that the study seems to be under-motivated. The authors could have made better use of the abstract, translational statement and introduction to explain the phenomenon more intimately and motivate their specific aim. These three sections briefly describe the pathological manifestations of defective Notch signalling without highlighting the possibilities of connecting their study with the explained disorders. This phenotype-motivated study thus lacks an organic flow in the main text. Throughout the results portion, the sections lack fluidity and it is not always intuitively possible to understand the motivation behind the next step.
While it was nice seeing affected whole kidney sections in the absence of Notch signalling, the authors could have tried looking at the cellular morphologies as well in this dominant-negative mastermind background.
Further, it was shown that Notch signalling was essential beyond SSB stage and acute inhibition also interfered with proper neural morphogenesis. Perhaps the authors could focus more on the specific role of Notch at these different stages in embryonic development. It could be included in the discussion, if speculatory.
The reason for looking at cilia and centrosomes in figure 4 could have been explained better, as it seems like a huge jump coming from the importance of Notch in spheroid formation. An experiment or comment regarding cilia numbers in wild-type versus Notch inactivated background is important and seems to be ignored. Additionally, the authors should mention if renal epithelial cell morphology was at all affected due to Notch inhibition.
Further explanation regarding defects in ciliary ultrastructure was required to explain the phenotypes seen in EM images (figure 6). The consequences of the altered 6/8+1 arrangement were overlooked. Maybe a reference to a complimentary study highlighting this arrangement and its implications would have helped in gaining a better understanding of a Notch-dependent basis for ciliopathies.
The role of Akap12 in cilia length was explored in a rather shallow fashion. Additional experiments or comments are needed addressing the importance of Akap12 repression for cilia length maintenance. While they mentioned Aurora A and Plk1 as proteins complexing with Akap12, their possible relevance in this study was never commented on. Additionally, it would be worthwhile exploring the effects of Akap12 downregulation on cilia length and numbers. Will there be a decrease in both? Does Notch signalling participate in maintaining a certain level of Akap12 for normal ciliogenesis? Again, in this section, cellular imaging would aid in understanding the effect of Akap12 overexpression on tubule morphogenesis.
Additionally, taking kidney sections from mice overexpressing Akap12 would have shed some light on its consequent roles in renal cyst formation. This might have also helped in understanding the relation between cyst formation and ciliopathy due to abrogated Notch signalling.
Lastly, it would have been worthwhile taking samples from patients suffering from Alagille syndrome and assessing for Akap12 upregulation, ciliary, and centriolar defects for the purpose of this study. This would have helped bridge the translational gap that seems to have been overlooked since its introduction in the beginning.
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