Antagonistic Transcription Factors XAP5 and XAP5L Regulate Ciliary Transcriptional Programs during Spermatogenesis

Core Concepts

XAP5 and XAP5L are two conserved pairs of antagonistic transcription factors that coordinate the temporal and spatial regulation of ciliary gene expression during spermatogenesis.

Abstract

The content explores the roles of the transcription factors XAP5 and XAP5L in regulating ciliary gene expression during spermatogenesis in mice. Key highlights: XAP5 and XAP5L are evolutionarily conserved transcription factors that show distinct expression patterns during spermatogenesis. XAP5 is widely expressed, while XAP5L is specifically expressed in the testes. Mice lacking either XAP5 or XAP5L exhibit male infertility due to defects in spermatogenesis. XAP5 knockout leads to meiotic arrest, while XAP5L knockout results in sperm flagella malformation. Mechanistically, XAP5 positively regulates the expression of key ciliary transcription factors like FOXJ1 and RFX families during the early stages of spermatogenesis. In contrast, XAP5L acts as a transcriptional repressor of these ciliary regulators during the later spermiogenesis stage. The antagonistic functions of XAP5 and XAP5L coordinate the temporal and spatial control of ciliary gene expression programs required for proper spermatogenesis and sperm flagella formation. The findings provide new insights into how evolutionarily conserved transcription factors can regulate the dynamic transcriptional programs governing ciliogenesis in multicellular organisms.

Stats

Sperm total motility was significantly reduced in XAP5L KO mice compared to wildtype. Abnormal sperm morphology was significantly increased in XAP5L KO mice compared to wildtype.

Quotes

"XAP5 positively regulates the ciliary gene expression by activating the key regulators including FOXJ1 and RFX families during the early stage of spermatogenesis." "In contrast, XAP5L negatively regulates the expression of ciliary genes via repressing these ciliary transcription factors during the spermiogenesis stage."

Key Insights Distilled From

Control of ciliary transcriptional programs during spermatogenesis by antagonistic transcription factors

by Wang,W., Xin... at www.biorxiv.org 01-02-2024

https://www.biorxiv.org/content/10.1101/2024.01.01.573824v3

Deeper Inquiries

How do the upstream signaling pathways or developmental cues regulate the spatiotemporal expression of XAP5 and XAP5L during spermatogenesis?

During spermatogenesis, the spatiotemporal expression of XAP5 and XAP5L is likely regulated by specific upstream signaling pathways and developmental cues. These factors play a crucial role in coordinating the transcriptional programs that control ciliogenesis in male germ cells. Cell Type-Specific Transcription Factors: The expression of XAP5 and XAP5L in different testicular cell types suggests that cell type-specific transcription factors may regulate their expression. For example, spermatogonia-specific factors may control XAP5 expression, while pachytene spermatocyte-specific factors may regulate XAP5L expression. Hormonal Regulation: Hormones such as testosterone and follicle-stimulating hormone (FSH) are known to play key roles in spermatogenesis. These hormones may influence the expression of XAP5 and XAP5L through their downstream signaling pathways. Developmental Signaling Pathways: Signaling pathways involved in testicular development and spermatogenesis, such as the Wnt signaling pathway or the Notch signaling pathway, could potentially regulate the expression of XAP5 and XAP5L at different stages of germ cell development. Epigenetic Regulation: Epigenetic mechanisms, including DNA methylation and histone modifications, may also contribute to the spatiotemporal regulation of XAP5 and XAP5L expression during spermatogenesis. Feedback Loops: Feedback loops involving ciliary gene expression and ciliogenesis-related pathways may further fine-tune the expression of XAP5 and XAP5L in a spatiotemporal manner. Understanding how these upstream signaling pathways and developmental cues interact to regulate the expression of XAP5 and XAP5L will provide valuable insights into the molecular mechanisms underlying ciliogenesis during spermatogenesis.

What are the potential compensatory mechanisms or alternative pathways that could bypass the loss of XAP5/XAP5L to maintain ciliogenesis in other cell types or developmental contexts?

In the event of the loss of XAP5 and XAP5L, cells may activate compensatory mechanisms or alternative pathways to maintain ciliogenesis and ensure proper cellular functions. Some potential mechanisms include: Redundant Transcription Factors: Other transcription factors with overlapping functions or similar regulatory roles may compensate for the loss of XAP5 and XAP5L. These factors could activate ciliary gene expression and promote ciliogenesis in the absence of XAP5/XAP5L. Epigenetic Modifications: Cells may undergo epigenetic changes to modulate the expression of ciliary genes and promote ciliogenesis. This could involve alterations in DNA methylation patterns or histone modifications to activate alternative pathways. Post-Transcriptional Regulation: RNA-binding proteins or microRNAs may post-transcriptionally regulate the expression of ciliary genes in the absence of XAP5/XAP5L, allowing for the maintenance of ciliogenesis. Compensatory Signaling Pathways: Cells may activate compensatory signaling pathways that converge on key regulators of ciliogenesis to ensure the formation and function of cilia in the absence of XAP5 and XAP5L. Cellular Reprogramming: Under certain conditions, cells may undergo reprogramming to adopt alternative cell fates that do not rely on ciliogenesis for their functions, thereby bypassing the need for XAP5/XAP5L. By elucidating these compensatory mechanisms and alternative pathways, researchers can gain a better understanding of the robustness and flexibility of cellular processes like ciliogenesis in different cell types and developmental contexts.

Given the evolutionary conservation of XAP5, could its dysregulation contribute to the pathogenesis of human ciliopathies, such as the X-linked intellectual disability associated with rare XAP5 variants?

The evolutionary conservation of XAP5 suggests that its dysregulation could indeed contribute to the pathogenesis of human ciliopathies, including X-linked intellectual disability associated with rare XAP5 variants. Here's how XAP5 dysregulation may impact ciliopathies: Ciliary Dysfunction: XAP5 is involved in regulating ciliary gene expression and ciliogenesis. Dysregulation of XAP5 could lead to impaired ciliary function, affecting cellular processes dependent on cilia, such as signal transduction and cell movement. Developmental Defects: XAP5 is crucial for spermatogenesis in mice, indicating its importance in male fertility. Dysregulation of XAP5 in humans could lead to developmental defects in the male reproductive system, potentially causing infertility. Neurological Implications: XAP5 variants have been associated with X-linked intellectual disability. Dysregulation of XAP5 may impact neuronal development and function, contributing to cognitive impairments seen in intellectual disability. Ciliopathy Manifestations: Ciliopathies are characterized by a wide range of clinical manifestations, including renal abnormalities, retinal degeneration, and skeletal defects. Dysregulation of XAP5 could exacerbate ciliopathy symptoms by disrupting ciliary structure and function. Therapeutic Targets: Understanding the role of XAP5 in ciliopathies could identify potential therapeutic targets for treating these disorders. Targeting XAP5-related pathways may offer new avenues for intervention in ciliopathy patients. In conclusion, the dysregulation of XAP5, a conserved transcription factor involved in ciliogenesis, could indeed contribute to the pathogenesis of human ciliopathies, including X-linked intellectual disability associated with rare XAP5 variants. Further research into the molecular mechanisms underlying XAP5-related disorders is essential for developing targeted therapies and improving patient outcomes.