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Biomedicines
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Connexins and Pannexins in Embryonic and Fetal Development
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Connexins and Pannexins in Embryonic and Fetal Development

A special issue of Biomedicines (ISSN 2227-9059). This special issue belongs to the section "Cell Biology and Pathology".

Deadline for manuscript submissions: closed (30 September 2022) | Viewed by 14578

Special Issue Editor

Prof. Dr. Natalija Filipović

E-Mail Website
Guest Editor
Department of Anatomy, Histology and Embryology, University of Split School of Medicine, Šoltanska 2, 21000 Split, Croatia
Interests: microvascular and macrovascular complications of diabetes; diabetic nephropathy; renal physiology and pathology; gene expression during embryonic and foetal development; kidneys and urinary system
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

Embryonic development is a complex, carefully regulated process in which, from a single cell, the formation of a complex multicellular organism occurs. An astonishing level of spatial and temporal coordination of different cellular processes, such as proliferation, migration, differentiation, and tissue formation, is necessary for proper development. This coordination is achieved through the operation of different signaling pathways. In addition, there is a growing body of evidence that points to the important roles of direct intercellular communication in early developmental processes. Connexins and pannexins are transmembrane proteins that form large pore channels, where connexin-made channels also make gap junctions, enabling a direct cell-to-cell and paracrine communication between cells via the exchange of ions, metabolites, and second messengers.

Due to their important role in intercellular communication, mutations of gene encoding connexin proteins have been related to several human diseases and developmental disturbances. In addition, the role of connexins in female infertility, through their influence on the development of the germline, oogenesis, implantation, and decidualization, is extensively studied.

Concerning their important roles in embryonal development, disturbances in connexin/pannexin expression might lead to pathological development and result in malformations and diseases. Despite the extensive research that has recently been carried out, our knowledge of this topic is still limited. Hence, we cordially invite investigators to submit review articles or original research that contribute to our understanding of this complex field of general interest.

Prof. Dr. Natalija Filipović
Guest Editor

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Keywords

  • embryonal and fetal development
  • infertility
  • connexins
  • pannexins
  • gap junctions

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Published Papers (6 papers)

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Research

Jump to: Review

22 pages, 6269 KiB  
Article
Connexins and Pannexins—Similarities and Differences According to the FOD-M Model
by Irena Roterman, Katarzyna Stapor, Piotr Fabian and Leszek Konieczny
Biomedicines 2022, 10(7), 1504; https://doi.org/10.3390/biomedicines10071504 - 25 Jun 2022
Cited by 8 | Viewed by 1531
Abstract
Connexins and pannexins are the transmembrane proteins of highly distinguished biological activity in the form of transport of molecules and electrical signals. Their common role is to connect the external environment with the cytoplasm of the cell, while connexin is also able to [...] Read more.
Connexins and pannexins are the transmembrane proteins of highly distinguished biological activity in the form of transport of molecules and electrical signals. Their common role is to connect the external environment with the cytoplasm of the cell, while connexin is also able to link two cells together allowing the transport from one to another. The analysis presented here aims to identify the similarities and differences between connexin and pannexin. As a comparative criterion, the hydrophobicity distribution in the structure of the discussed proteins was used. The comparative analysis is carried out with the use of a mathematical model, the FOD-M model (fuzzy oil drop model in its Modified version) expressing the specificity of the membrane’s external field, which in the case of the discussed proteins is significantly different from the external field for globular proteins in the polar environment of water. The characteristics of the external force field influence the structure of protein allowing the activity in a different environment. Full article
(This article belongs to the Special Issue Connexins and Pannexins in Embryonic and Fetal Development)
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15 pages, 4993 KiB  
Article
The Reduction in Microtubule Arrays Caused by the Dysplasia of the Non-Centrosomal Microtubule-Organizing Center Leads to a Malformed Organ of Corti in the Cx26-Null Mouse
by Yue Qiu, Kai Xu, Le Xie, Sen Chen and Yu Sun
Biomedicines 2022, 10(6), 1364; https://doi.org/10.3390/biomedicines10061364 - 9 Jun 2022
Cited by 2 | Viewed by 1776
Abstract
Mutations in the GJB2 gene account for approximately 20–50% of all non-syndromic hereditary deafness cases. The malformed organ of Corti (OC) was observed in different Cx26-null mouse models, which was mainly caused by the developmental arrest of pillar cells (PCs). However, the mechanism [...] Read more.
Mutations in the GJB2 gene account for approximately 20–50% of all non-syndromic hereditary deafness cases. The malformed organ of Corti (OC) was observed in different Cx26-null mouse models, which was mainly caused by the developmental arrest of pillar cells (PCs). However, the mechanism of developmental abnormalities in PCs caused by Cx26 deletion is still unclear. In this study, the ultrastructure of PCs at different postnatal days was observed in Cx26-null mice. Knockout of cochlear Cx26 led to the malformed assembly of non-centrosomal microtubule-organizing centers (MTOCs) far from the centrosome rather than near the centrosome. Additionally, the microtubule (MT) arrays emitted by abnormal non-centrosomal MTOCs were significantly reduced. In addition, we found that the protein expression of calmodulin-regulated, spectrin-associated protein2 (camsap2), a microtubule minus-end targeting protein associated with the organization of non-centrosomal MTs, was decreased in juvenile PCs in the Cx26-null group. Our results indicated that the malformation of non-centrosomal MTOCs in cochlear PCs might lead to the corresponding MTs’ failure to be captured and anchored in Cx26-null mice, which results in the deformity of OC. Additionally, this abnormal developmental process might be correlated with the reduced expression of camsap2 caused by Cx26 deletion in the early developmental stage. Full article
(This article belongs to the Special Issue Connexins and Pannexins in Embryonic and Fetal Development)
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20 pages, 3866 KiB  
Article
Expression of Pannexin 1 in the Human Kidney during Embryonal, Early Fetal and Postnatal Development and Its Prognostic Significance in Diabetic Nephropathy
by Ivo Jeličić, Katarina Vukojević, Anita Racetin, Davor Čarić, Merica Glavina Durdov, Mirna Saraga-Babić and Natalija Filipović
Biomedicines 2022, 10(5), 944; https://doi.org/10.3390/biomedicines10050944 - 20 Apr 2022
Cited by 5 | Viewed by 2234
Abstract
Pannexins are transmembrane glycoproteins that constitute channels involved in purinergic signaling through ATP release from cells in various physiological and pathological processes. In this study, the distribution of Panx1 expression in different cell populations of healthy postnatal human kidneys and during human embryonic [...] Read more.
Pannexins are transmembrane glycoproteins that constitute channels involved in purinergic signaling through ATP release from cells in various physiological and pathological processes. In this study, the distribution of Panx1 expression in different cell populations of healthy postnatal human kidneys and during human embryonic and early fetal development was investigated by double immunohistochemistry. In addition, the glomerular and tubular expression of Panx1 was examined in patients with type 2 diabetes mellitus (DM2) and the control group, and renal Panx1 expression was correlated with serum creatinine. In the 6th week of embryonic development (DW), Panx1 expression was found in mesonephric glomeruli and mesonephric tubules. At the transition from 6th to 7th DW, Panx1 immunoreactivity was found in the mesonephric tubules and mesonephric duct, as well as in the metanephric ureteric bud and ampullae. In the 7th DW, strong Panx1 immunoreactivity was observed in the developing ureteric bud in the metanephros, whereas no Panx1 immunoreactivity was found in the metanephric cup. In the 8th DW, Panx1 expression was also found in the ureteric bud of the metanephros, the renal vesicle and comma-shaped nephron, and the epithelial cells of Bowman’s capsule. Expression of Panx1 was found at an early stage in both the paramesonephric duct and the mesonephric duct and diminished toward the 8th DW. During the 6th–10th DW, colocalization of Panx1 with alpha smooth actin (aSMA) was found in developing blood vessels. In the postnatal kidney, strong Panx1 immunoreactivity was present in medullary and cortical collecting duct cells, renin-producing cells, and proximal tubules. Very weak Panx1 immunoreactivity was found in certain distal tubule cells and the thin descending limbs of the loop of Henle. Panx1 immunoreactivity was also found in nephrin-immunoreactive podocytes. Panx1 was not colocalized with aSMA immunoreactivity in the vessels of the postnatal human kidney, but it was present in the endothelium. A significant positive correlation was found between Panx1 expression in glomeruli and serum creatinine only in diabetic patients and was not found in the nondiabetic group. The spatiotemporal expression of Panx1 during the early stages of human kidney development supports its possible role in cellular differentiation, migration, and positioning in the developing human kidney. In addition, our data suggest that glomerular Panx1 expression is a potential indicator of worsening renal function in patients with type 2 diabetes. Full article
(This article belongs to the Special Issue Connexins and Pannexins in Embryonic and Fetal Development)
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17 pages, 3946 KiB  
Article
The Interplay of Cx26, Cx32, Cx37, Cx40, Cx43, Cx45, and Panx1 in Inner-Ear Development of Yotari (dab1−/−) Mice and Humans
by Josip Lesko, Pejana Rastović, Josip Mišković, Violeta Šoljić, Vlatka Paštar, Zdenka Zovko, Natalija Filipović, Yu Katsuyama, Mirna Saraga-Babić and Katarina Vukojević
Biomedicines 2022, 10(3), 589; https://doi.org/10.3390/biomedicines10030589 - 3 Mar 2022
Cited by 3 | Viewed by 2507
Abstract
We investigated DAB1-protein deficiency in the inner-ear development of yotari in comparison to humans and wild-type (wt) mice by immunofluorescence for the expression of connexins (Cxs) and the pannexin Panx1. The spatial and temporal dynamics of Cx26, Cx32, Cx37, Cx40, Cx43, Cx45, and [...] Read more.
We investigated DAB1-protein deficiency in the inner-ear development of yotari in comparison to humans and wild-type (wt) mice by immunofluorescence for the expression of connexins (Cxs) and the pannexin Panx1. The spatial and temporal dynamics of Cx26, Cx32, Cx37, Cx40, Cx43, Cx45, and Panx1 were determined in the sixth and eighth weeks of human development and at the corresponding mouse embryonic E13.5 and E15.5, in order to examine gap junction intercellular communication (GJIC) and hemichannel formation. The quantification of the area percentage covered by positive signal was performed for the epithelium and mesenchyme of the cochlear and semicircular ducts and is expressed as the mean ± SD. The data were analysed by one-way ANOVA. Almost all of the examined Cxs were significantly decreased in the cochlear and semicircular ducts of yotari compared to wt and humans, except for Cx32, which was significantly higher in yotari. Cx40 dominated in human inner-ear development, while yotari and wt had decreased expression. The Panx1 expression in yotari was significantly lower than that in the wt and human inner ear, except at E13.5 in the mesenchyme of the wt and epithelium and mesenchyme of humans. Our results emphasize the relevance of GJIC during the development of vestibular and cochlear functions, where they can serve as potential therapeutic targets in inner-ear impairments. Full article
(This article belongs to the Special Issue Connexins and Pannexins in Embryonic and Fetal Development)
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Review

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29 pages, 2296 KiB  
Review
Connexins and Pannexins: Important Players in Neurodevelopment, Neurological Diseases, and Potential Therapeutics
by Daniela Baracaldo-Santamaría, María Gabriela Corrales-Hernández, Maria Camila Ortiz-Vergara, Valeria Cormane-Alfaro, Ricardo-Miguel Luque-Bernal, Carlos-Alberto Calderon-Ospina and Juan-Fernando Cediel-Becerra
Biomedicines 2022, 10(9), 2237; https://doi.org/10.3390/biomedicines10092237 - 9 Sep 2022
Cited by 4 | Viewed by 3036
Abstract
Cell-to-cell communication is essential for proper embryonic development and its dysfunction may lead to disease. Recent research has drawn attention to a new group of molecules called connexins (Cxs) and pannexins (Panxs). Cxs have been described for more than forty years as pivotal [...] Read more.
Cell-to-cell communication is essential for proper embryonic development and its dysfunction may lead to disease. Recent research has drawn attention to a new group of molecules called connexins (Cxs) and pannexins (Panxs). Cxs have been described for more than forty years as pivotal regulators of embryogenesis; however, the exact mechanism by which they provide this regulation has not been clearly elucidated. Consequently, Cxs and Panxs have been linked to congenital neurodegenerative diseases such as Charcot-Marie-Tooth disease and, more recently, chronic hemichannel opening has been associated with adult neurodegenerative diseases (e.g., Alzheimer’s disease). Cell-to-cell communication via gap junctions formed by hexameric assemblies of Cxs, known as connexons, is believed to be a crucial component in developmental regulation. As for Panxs, despite being topologically similar to Cxs, they predominantly seem to form channels connecting the cytoplasm to the extracellular space and, despite recent research into Panx1 (Pannexin 1) expression in different regions of the brain during the embryonic phase, it has been studied to a lesser degree. When it comes to the nervous system, Cxs and Panxs play an important role in early stages of neuronal development with a wide span of action ranging from cellular migration during early stages to neuronal differentiation and system circuitry formation. In this review, we describe the most recent available evidence regarding the molecular and structural aspects of Cx and Panx channels, their role in neurodevelopment, congenital and adult neurological diseases, and finally propose how pharmacological modulation of these channels could modify the pathogenesis of some diseases. Full article
(This article belongs to the Special Issue Connexins and Pannexins in Embryonic and Fetal Development)
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21 pages, 1110 KiB  
Review
Connexins, Pannexins and Gap Junctions in Perinatal Brain Injury
by Alice McDouall, Kelly Q. Zhou, Laura Bennet, Colin R. Green, Alistair J. Gunn and Joanne O. Davidson
Biomedicines 2022, 10(6), 1445; https://doi.org/10.3390/biomedicines10061445 - 18 Jun 2022
Cited by 2 | Viewed by 2666
Abstract
Perinatal brain injury secondary to hypoxia-ischemia and/or infection/inflammation remains a major cause of disability. Therapeutic hypothermia significantly improves outcomes, but in randomized controlled trials nearly half of infants still died or survived with disability, showing that additional interventions are needed. There is growing [...] Read more.
Perinatal brain injury secondary to hypoxia-ischemia and/or infection/inflammation remains a major cause of disability. Therapeutic hypothermia significantly improves outcomes, but in randomized controlled trials nearly half of infants still died or survived with disability, showing that additional interventions are needed. There is growing evidence that brain injury spreads over time from injured to previously uninjured regions of the brain. At least in part, this spread is related to opening of connexin hemichannels and pannexin channels, both of which are large conductance membrane channels found in many brain cells. Opening of these membrane channels releases adenosine triphosphate (ATP), and other neuroactive molecules, into the extracellular space. ATP has an important role in normal signaling, but pathologically can trigger the assembly of the multi-protein inflammasome complex. The inflammasome complex promotes activation of inflammatory caspases, and release of inflammatory cytokines. Overall, the connexin hemichannel appears to play a primary role in propagation of injury and chronic disease, and connexin hemichannel blockade has been shown to be neuroprotective in multiple animal models. Thus, there is potential for some blockers of connexin or pannexin channels to be developed into targeted interventions that could be used in conjunction with or separate to therapeutic hypothermia. Full article
(This article belongs to the Special Issue Connexins and Pannexins in Embryonic and Fetal Development)
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