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PAX Genes in Health and Diseases

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A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Genetics and Genomics".

Deadline for manuscript submissions: closed (15 March 2023) | Viewed by 33340

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Prof. Dr. Michael Eccles

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Department of Pathology, Dunedin School of Medicine, University of Otago, Dunedin 9016, New Zealand
Interests: genomics; epigenomics; melanomas; human cancer; PAX genes; transcriptomic
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Special Issue Information

Dear Colleagues,

Since their initial discovery, and subsequent characterization in humans, Paired box (PAX) genes have emerged as players with key roles in health and disease. For example, PAX genes are essential for the formation of many tissues during fetal development, while in adults, PAX genes help to maintain the homeostasis of several organs and tissues. Moreover, mutations in PAX genes cause multiple hereditary, as well as sporadic childhood and adult human diseases, including cancer. PAX gene expression levels are critically involved in human health and disease, ranging from understanding the body’s response to certain drugs, like tamoxifen, to the onset of polycystic kidney disease, cancer, as well as many other diseases.

This Special Issue calls for both original articles as well as reviews on the role of PAX genes in health and disease, and as therapeutic targets, or as diagnostic markers for disease monitoring, or disease prevention. PAX genes arose during evolution, possibly very early in the evolution of the first unicellular to multicellular eukaryotes. Therefore, PAX genes could have facilitated, in multicellular organisms, the evolution of central nervous systems, and other key organs and sensory structures, such as eyes. Therefore, this Special Issue also calls for articles that address the evolution of PAX genes, with a particular emphasis on the provision of novel insights into health and disease.

Prof. Dr. Michael Eccles
Guest Editor

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Keywords

PAX gene
developmental control gene
organogenesis
DNA-binding
transcription factor
paired box gene family
paired domain

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Published Papers (9 papers)

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Research

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16 pages, 4587 KiB

Open AccessArticle

Co-Expression of Multiple PAX Genes in Renal Cell Carcinoma (RCC) and Correlation of High PAX Expression with Favorable Clinical Outcome in RCC Patients

by Lei Li, Caiyun G. Li, Suzan N. Almomani, Sultana Mehbuba Hossain and Michael R. Eccles

Int. J. Mol. Sci. 2023, 24(14), 11432; https://doi.org/10.3390/ijms241411432 - 14 Jul 2023

Cited by 4 | Viewed by 2206

Abstract

Renal cell carcinoma (RCC) is the most common form of kidney cancer, consisting of multiple distinct subtypes. RCC has the highest mortality rate amongst the urogenital cancers, with kidney renal clear cell carcinoma (KIRC), kidney renal papillary cell carcinoma (KIRP), and kidney chromophobe carcinoma (KICH) being the most common subtypes. The Paired-box (PAX) gene family encodes transcription factors, which orchestrate multiple processes in cell lineage determination during embryonic development and organogenesis. Several PAX genes have been shown to be expressed in RCC following its onset and progression. Here, we performed real-time quantitative polymerase chain reaction (RT-qPCR) analysis on a series of human RCC cell lines, revealing significant co-expression of PAX2, PAX6, and PAX8. Knockdown of PAX2 or PAX8 mRNA expression using RNA interference (RNAi) in the A498 RCC cell line resulted in inhibition of cell proliferation, which aligns with our previous research, although no reduction in cell proliferation was observed using a PAX2 small interfering RNA (siRNA). We downloaded publicly available RNA-sequencing data and clinical histories of RCC patients from The Cancer Genome Atlas (TCGA) database. Based on the expression levels of PAX2, PAX6, and PAX8, RCC patients were categorized into two PAX expression subtypes, PAXClusterA and PAXClusterB, exhibiting significant differences in clinical characteristics. We found that the PAXClusterA expression subgroup was associated with favorable clinical outcomes and better overall survival. These findings provide novel insights into the association between PAX gene expression levels and clinical outcomes in RCC patients, potentially contributing to improved treatment strategies for RCC. Full article

(This article belongs to the Special Issue PAX Genes in Health and Diseases)

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10 pages, 4929 KiB

Open AccessArticle

PAX2 and CAKUT Phenotypes: Report on Two New Variants and a Review of Mutations from the Leiden Open Variation Database

by Susanna Negrisolo and Elisa Benetti

Int. J. Mol. Sci. 2023, 24(4), 4165; https://doi.org/10.3390/ijms24044165 - 19 Feb 2023

Cited by 3 | Viewed by 2225

Abstract

PAX2 is a transcription factor expressed during embryogenesis in the eye, ear, CNS, and genitourinary tract, and is one of the major regulators of kidney development. Mutations in this gene are associated with papillorenal syndrome (PAPRS), a genetic condition characterized by optic nerve dysplasia and renal hypo/dysplasia. In the last 28 years, many cohort studies and case reports highlighted PAX2’s involvement in a large spectrum of kidney malformations and diseases, with or without eye abnormalities, defining the phenotypes associated with PAX2 variants as “PAX2-related disorders”. Here, we reported two new sequence variations and reviewed PAX2 mutations annotated on the Leiden Open Variation Database 3.0. DNA was extracted from the peripheral blood of 53 pediatric patients with congenital abnormalities of the kidney and urinary tract (CAKUT). PAX2 gene-coding exonic and flanking intronic regions were sequenced with Sanger technology. Two unrelated patients and two twins carrying one known and two unknown PAX2 variations were observed. The frequency of PAX2-related disorders in this cohort was 5.8%, considering all CAKUT phenotypes (16.7% in the PAPRS phenotype and 2.5% in non-syndromic CAKUT). Although PAX2 mutations have a higher frequency in patients with PAPRS or non-syndromic renal hypoplasia, from the review of variants reported to date in LOVD3, PAX2-related disorders are detected in pediatric patients with other CAKUT phenotypes. In our study, only one patient had a CAKUT without an ocular phenotype, but his twin had both renal and ocular involvement, confirming the extreme inter- and intrafamilial phenotypic variability. Full article

(This article belongs to the Special Issue PAX Genes in Health and Diseases)

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15 pages, 993 KiB

Open AccessArticle

Minigene Splicing Assays and Long-Read Sequencing to Unravel Pathogenic Deep-Intronic Variants in PAX6 in Congenital Aniridia

by Alejandra Tamayo, Gonzalo Núñez-Moreno, Carolina Ruiz, Julie Plaisancie, Alejandra Damian, Jennifer Moya, Nicolas Chassaing, Patrick Calvas, Carmen Ayuso, Pablo Minguez and Marta Corton

Int. J. Mol. Sci. 2023, 24(2), 1562; https://doi.org/10.3390/ijms24021562 - 13 Jan 2023

Cited by 3 | Viewed by 4137

Abstract

PAX6 haploinsufficiency causes aniridia, a congenital eye disorder that involves the iris, and foveal hypoplasia. Comprehensive screening of the PAX6 locus, including the non-coding regions, by next-generation sequencing revealed four deep-intronic variants with potential effects on pre-RNA splicing. Nevertheless, without a functional analysis, their pathogenicity could not be established. We aimed to decipher their impact on the canonical PAX6 splicing using in vitro minigene splicing assays and nanopore-based long-read sequencing. Two multi-exonic PAX6 constructs were generated, and minigene assays were carried out. An aberrant splicing pattern was observed for two variants in intron 6, c.357+136G>A and c.357+334G>A. In both cases, several exonization events, such as pseudoexon inclusions and partial intronic retention, were observed due to the creation or activation of new/cryptic non-canonical splicing sites, including a shared intronic donor site. In contrast, two variants identified in intron 11, c.1032+170A>T and c.1033-275A>C, seemed not to affect splicing processes. We confirmed the high complexity of alternative splicing of PAX6 exon 6, which also involves unreported cryptic intronic sites. Our study highlights the importance of integrating functional studies into diagnostic algorithms to decipher the potential implication of non-coding variants, usually classified as variants of unknown significance, thus allowing variant reclassification to achieve a conclusive genetic diagnosis. Full article

(This article belongs to the Special Issue PAX Genes in Health and Diseases)

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Review

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12 pages, 716 KiB

Open AccessReview

Pax4 in Health and Diabetes

by Jenna Ko, Vivian A. Fonseca and Hongju Wu

Int. J. Mol. Sci. 2023, 24(9), 8283; https://doi.org/10.3390/ijms24098283 - 5 May 2023

Cited by 6 | Viewed by 2403

Abstract

Paired box 4 (Pax4) is a key transcription factor involved in the embryonic development of the pancreatic islets of Langerhans. Consisting of a conserved paired box domain and a homeodomain, this transcription factor plays an essential role in early endocrine progenitor cells, where it is necessary for cell-fate commitment towards the insulin-secreting β cell lineage. Knockout of Pax4 in animal models leads to the absence of β cells, which is accompanied by a significant increase in glucagon-producing α cells, and typically results in lethality within days after birth. Mutations in Pax4 that cause an impaired Pax4 function are associated with diabetes pathogenesis in humans. In adulthood, Pax4 expression is limited to a distinct subset of β cells that possess the ability to proliferate in response to heightened metabolic needs. Upregulation of Pax4 expression is known to promote β cell survival and proliferation. Additionally, ectopic expression of Pax4 in pancreatic islet α cells or δ cells has been found to generate functional β-like cells that can improve blood glucose regulation in experimental diabetes models. Therefore, Pax4 represents a promising therapeutic target for the protection and regeneration of β cells in the treatment of diabetes. The purpose of this review is to provide a thorough and up-to-date overview of the role of Pax4 in pancreatic β cells and its potential as a therapeutic target for diabetes. Full article

(This article belongs to the Special Issue PAX Genes in Health and Diseases)

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24 pages, 3037 KiB

Open AccessReview

The Pleiotropy of PAX5 Gene Products and Function

by Parinaz Nasri Nasrabadi, Danick Martin, Ehsan Gharib and Gilles A. Robichaud

Int. J. Mol. Sci. 2022, 23(17), 10095; https://doi.org/10.3390/ijms231710095 - 3 Sep 2022

Cited by 15 | Viewed by 4347

Abstract

PAX5, a member of the Paired Box (PAX) transcription factor family, is an essential factor for B-lineage identity during lymphoid differentiation. Mechanistically, PAX5 controls gene expression profiles, which are pivotal to cellular processes such as viability, proliferation, and differentiation. Given its crucial function in B-cell development, PAX5 aberrant expression also correlates with hallmark cancer processes leading to hematological and other types of cancer lesions. Despite the well-established association of PAX5 in the development, maintenance, and progression of cancer disease, the use of PAX5 as a cancer biomarker or therapeutic target has yet to be implemented. This may be partly due to the assortment of PAX5 expressed products, which layers the complexity of their function and role in various regulatory networks and biological processes. In this review, we provide an overview of the reported data describing PAX5 products, their regulation, and function in cellular processes, cellular biology, and neoplasm. Full article

(This article belongs to the Special Issue PAX Genes in Health and Diseases)

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19 pages, 6640 KiB

Open AccessReview

PAX Genes in Cardiovascular Development

by Rebecca E. Steele, Rachel Sanders, Helen M. Phillips and Simon D. Bamforth

Int. J. Mol. Sci. 2022, 23(14), 7713; https://doi.org/10.3390/ijms23147713 - 12 Jul 2022

Cited by 5 | Viewed by 2922

Abstract

The mammalian heart is a four-chambered organ with systemic and pulmonary circulations to deliver oxygenated blood to the body, and a tightly regulated genetic network exists to shape normal development of the heart and its associated major arteries. A key process during cardiovascular morphogenesis is the septation of the outflow tract which initially forms as a single vessel before separating into the aorta and pulmonary trunk. The outflow tract connects to the aortic arch arteries which are derived from the pharyngeal arch arteries. Congenital heart defects are a major cause of death and morbidity and are frequently associated with a failure to deliver oxygenated blood to the body. The Pax transcription factor family is characterised through their highly conserved paired box and DNA binding domains and are crucial in organogenesis, regulating the development of a wide range of cells, organs and tissues including the cardiovascular system. Studies altering the expression of these genes in murine models, notably Pax3 and Pax9, have found a range of cardiovascular patterning abnormalities such as interruption of the aortic arch and common arterial trunk. This suggests that these Pax genes play a crucial role in the regulatory networks governing cardiovascular development. Full article

(This article belongs to the Special Issue PAX Genes in Health and Diseases)

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18 pages, 1745 KiB

Open AccessReview

PAX8 in the Junction between Development and Tumorigenesis

by Reli Rachel Kakun, Zohar Melamed and Ruth Perets

Int. J. Mol. Sci. 2022, 23(13), 7410; https://doi.org/10.3390/ijms23137410 - 3 Jul 2022

Cited by 9 | Viewed by 4199

Abstract

Normal processes of embryonic development and abnormal transformation to cancer have many parallels, and in fact many aberrant cancer cell capabilities are embryonic traits restored in a distorted, unorganized way. Some of these capabilities are cell autonomous, such as proliferation and resisting apoptosis, while others involve a complex interplay with other cells that drives significant changes in neighboring cells. The correlation between embryonic development and cancer is driven by shared proteins. Some embryonic proteins disappear after embryogenesis in adult differentiated cells and are restored in cancer, while others are retained in adult cells, acquiring new functions upon transformation to cancer. Many embryonic factors embraced by cancer cells are transcription factors; some are master regulators that play a major role in determining cell fate. The paired box (PAX) domain family of developmental transcription factors includes nine members involved in differentiation of various organs. All paired box domain proteins are involved in different cancer types carrying pro-tumorigenic or anti-tumorigenic roles. This review focuses on PAX8, a master regulator of transcription in embryonic development of the thyroid, kidney, and male and female genital tracts. We detail the role of PAX8 in each of these organ systems, describe its role during development and in the adult if known, and highlight its pro-tumorigenic role in cancers that emerge from PAX8 expressing organs. Full article

(This article belongs to the Special Issue PAX Genes in Health and Diseases)

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19 pages, 2707 KiB

Open AccessReview

Thirty Years’ History since the Discovery of Pax6: From Central Nervous System Development to Neurodevelopmental Disorders

by Shohei Ochi, Shyu Manabe, Takako Kikkawa and Noriko Osumi

Int. J. Mol. Sci. 2022, 23(11), 6115; https://doi.org/10.3390/ijms23116115 - 30 May 2022

Cited by 22 | Viewed by 5809

Abstract

Pax6 is a sequence-specific DNA binding transcription factor that positively and negatively regulates transcription and is expressed in multiple cell types in the developing and adult central nervous system (CNS). As indicated by the morphological and functional abnormalities in spontaneous Pax6 mutant rodents, Pax6 plays pivotal roles in various biological processes in the CNS. At the initial stage of CNS development, Pax6 is responsible for brain patterning along the anteroposterior and dorsoventral axes of the telencephalon. Regarding the anteroposterior axis, Pax6 is expressed inversely to Emx2 and Coup-TF1, and Pax6 mutant mice exhibit a rostral shift, resulting in an alteration of the size of certain cortical areas. Pax6 and its downstream genes play important roles in balancing the proliferation and differentiation of neural stem cells. The Pax6 gene was originally identified in mice and humans 30 years ago via genetic analyses of the eye phenotypes. The human PAX6 gene was discovered in patients who suffer from WAGR syndrome (i.e., Wilms tumor, aniridia, genital ridge defects, mental retardation). Mutations of the human PAX6 gene have also been reported to be associated with autism spectrum disorder (ASD) and intellectual disability. Rodents that lack the Pax6 gene exhibit diverse neural phenotypes, which might lead to a better understanding of human pathology and neurodevelopmental disorders. This review describes the expression and function of Pax6 during brain development, and their implications for neuropathology. Full article

(This article belongs to the Special Issue PAX Genes in Health and Diseases)

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14 pages, 2397 KiB

Open AccessReview

PAX9 in Cancer Development

by Xiaoxin Chen, Yahui Li, Chorlada Paiboonrungruang, Yong Li, Heiko Peters, Ralf Kist and Zhaohui Xiong

Int. J. Mol. Sci. 2022, 23(10), 5589; https://doi.org/10.3390/ijms23105589 - 17 May 2022

Cited by 8 | Viewed by 3232

Abstract

Paired box 9 (PAX9) is a transcription factor of the PAX family functioning as both a transcriptional activator and repressor. Its functional roles in the embryonic development of various tissues and organs have been well studied. However, its roles and molecular mechanisms in cancer development are largely unknown. Here, we review the current understanding of PAX9 expression, upstream regulation of PAX9, and PAX9 downstream events in cancer development. Promoter hypermethylation, promoter SNP, microRNA, and inhibition of upstream pathways (e.g., NOTCH) result in PAX9 silencing or downregulation, whereas gene amplification and an epigenetic axis upregulate PAX9 expression. PAX9 may contribute to carcinogenesis through dysregulation of its transcriptional targets and related molecular pathways. In summary, extensive studies on PAX9 in its cellular and tissue contexts are warranted in various cancers, in particular, HNSCC, ESCC, lung cancer, and cervical SCC. Full article

(This article belongs to the Special Issue PAX Genes in Health and Diseases)

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