An ancient transcription factor functions as the master regulator of primary cilia formation
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eLife Assessment
This useful study identified XAP5 as an ancient transcriptional regulator critical for primary ciliogenesis. The evidence supporting the conceptual framework linking evolutionary conservation to functional specialization in primary ciliogenesis remains incomplete. This work will be of interest to developmental biologists and to those studying diseases caused by ciliopathies.
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Abstract
How ancient transcription factors are repurposed during evolution to drive the functional diversification of conserved organelles remains a fundamental question in biology. Although highly conserved in basic morphology, eukaryotic cilia vary extensively in their sizes and functions. Previously, we showed that an evolutionarily ancient transcription factor, X chromosome–associated protein 5 (Xap5), controls motile ciliogenic transcriptional programs during mouse spermatogenesis (Wang et al., 2025). Here we show that Xap5 functions as the master regulator of primary ciliogenesis. Xap5 associates with the nuclear protein Non-POU domain–containing octamer-binding protein (Nono) to form a regulatory module that directly binds and activates the transcription factors Sox5 and Sox9. Genetic ablation of Xap5 or Nono impairs primary ciliogenesis, and loss of Sox5 disrupts the downstream ciliogenic program, consistent with the established role of Sox9. Collectively, our results provide new insight into how complex ciliary transcription factor networks determine ciliary diversity during evolution, and suggest that defects in this regulatory axis may contribute to the etiology of human ciliopathies.
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eLife Assessment
This useful study identified XAP5 as an ancient transcriptional regulator critical for primary ciliogenesis. The evidence supporting the conceptual framework linking evolutionary conservation to functional specialization in primary ciliogenesis remains incomplete. This work will be of interest to developmental biologists and to those studying diseases caused by ciliopathies.
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Reviewer #1 (Public review):
Summary:
The authors have attempted to establish a role for XAP5, a transcriptional regulator they have previously identified for flagellar biogenesis in Chlamydomonas and mice, in primary cilia differentiation.
Strengths:
Genetic and biochemical analysis using a cultured mouse cell line, NIH3T3.
Weaknesses:
(1) The authors have ignored established data that, like in C. elegans and Drosophila, there is in vivo genetic evidence that primary cilia formation is regulated by the RFX transcriptional module (for example, PMID 19887680, PMID 29510665).
(2) The analysis with one mammalian cell line, NIH3T3, while done quite rigorously, is not sufficient. Also, the effect on cilia differentiation is very modest - a shortening of cilia length on XAP5, NONO and SOX5 knockout - which can happen for a variety of reasons, …
Reviewer #1 (Public review):
Summary:
The authors have attempted to establish a role for XAP5, a transcriptional regulator they have previously identified for flagellar biogenesis in Chlamydomonas and mice, in primary cilia differentiation.
Strengths:
Genetic and biochemical analysis using a cultured mouse cell line, NIH3T3.
Weaknesses:
(1) The authors have ignored established data that, like in C. elegans and Drosophila, there is in vivo genetic evidence that primary cilia formation is regulated by the RFX transcriptional module (for example, PMID 19887680, PMID 29510665).
(2) The analysis with one mammalian cell line, NIH3T3, while done quite rigorously, is not sufficient. Also, the effect on cilia differentiation is very modest - a shortening of cilia length on XAP5, NONO and SOX5 knockout - which can happen for a variety of reasons, especially in culture conditions. In my view, this relatively mild phenotype does not establish that the XAP5/NONO and SOX5 axis is an important regulator of primary cilia differentiation.
(3) The lack of any data that validates the findings in the model vertebrate is a major weakness of this paper. Validation using clean genetics (whole body knockouts or tissue-specific conditional knockouts) is absolutely essential for these data to be acceptable.
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Reviewer #2 (Public review):
Summary:
This study investigates how evolutionarily conserved transcription factors are repurposed to regulate the functional diversification of cilia. Building on previous work identifying Xap5 as a regulator of motile ciliogenesis during spermatogenesis, the authors now propose a broader role for Xap5 as a master regulator of primary ciliogenesis. Through extensive mechanistic analyses, they identify an Xap5-NONO-SOX transcriptional axis and suggest that this module contributes to ciliary diversity and may be implicated in ciliopathies.
Overall, the work addresses an important and timely question regarding the transcriptional control of primary ciliogenesis. However, additional evidence is required to fully support the proposed conceptual framework linking evolutionary conservation to functional …
Reviewer #2 (Public review):
Summary:
This study investigates how evolutionarily conserved transcription factors are repurposed to regulate the functional diversification of cilia. Building on previous work identifying Xap5 as a regulator of motile ciliogenesis during spermatogenesis, the authors now propose a broader role for Xap5 as a master regulator of primary ciliogenesis. Through extensive mechanistic analyses, they identify an Xap5-NONO-SOX transcriptional axis and suggest that this module contributes to ciliary diversity and may be implicated in ciliopathies.
Overall, the work addresses an important and timely question regarding the transcriptional control of primary ciliogenesis. However, additional evidence is required to fully support the proposed conceptual framework linking evolutionary conservation to functional specialization.
Strengths:
(1) Addresses a timely and fundamental question in cilia biology.
(2) Extends Xap5 function beyond motile ciliogenesis.
(3) Identifies a novel regulatory axis (Xap5-NONO-SOX).
(4) Combines multiple well-designed mechanistic approaches.
(5) Proposes an interesting conceptual framework linking evolution and ciliogenesis.
Weaknesses:
(1) Specificity for primary ciliogenesis not demonstrated.
(2) No data on motile ciliogenesis in somatic MCCs.
(3) Conclusions drawn from NIH/3T3 cells (murine stromal cells).
(4) GC-rich motif identified but underexplored.
(5) Link to ciliopathies is speculative.
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