Pub Date : 2025-05-20DOI: 10.1016/j.gde.2025.102357
Peiheng Liu , Serene Mattis , Thorold W Theunissen
Stem cell–based embryo models have taken the scientific community by storm as they enable investigation of previously inaccessible stages of human development. Here, we discuss how stem cell–based embryo and placenta models can shine a light on two elusive and intertwined aspects of human development that are critical for successful pregnancy: the implantation of the blastocyst into the endometrium and the subsequent invasion of placental villi deep inside the maternal tissues. Both of these processes are mediated by the trophoblast lineage, which is specified in the preimplantation embryo and can be modeled using naïve pluripotent stem cells. We review how embryo and placenta models built from naïve stem cells can be leveraged to obtain mechanistic insights into human implantation and trophoblast invasion.
{"title":"Stem cell models of human embryo implantation and trophoblast invasion","authors":"Peiheng Liu , Serene Mattis , Thorold W Theunissen","doi":"10.1016/j.gde.2025.102357","DOIUrl":"10.1016/j.gde.2025.102357","url":null,"abstract":"<div><div>Stem cell–based embryo models have taken the scientific community by storm as they enable investigation of previously inaccessible stages of human development. Here, we discuss how stem cell–based embryo and placenta models can shine a light on two elusive and intertwined aspects of human development that are critical for successful pregnancy: the implantation of the blastocyst into the endometrium and the subsequent invasion of placental villi deep inside the maternal tissues. Both of these processes are mediated by the trophoblast lineage, which is specified in the preimplantation embryo and can be modeled using naïve pluripotent stem cells. We review how embryo and placenta models built from naïve stem cells can be leveraged to obtain mechanistic insights into human implantation and trophoblast invasion.</div></div>","PeriodicalId":50606,"journal":{"name":"Current Opinion in Genetics & Development","volume":"93 ","pages":"Article 102357"},"PeriodicalIF":3.7,"publicationDate":"2025-05-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144088910","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-05-15DOI: 10.1016/j.gde.2025.102358
Hannah M Deutsch , Yuanquan Song , Dong Li
Neurodevelopment requires complex spatiotemporal expression, which heavily relies on proper RNA splicing. The spliceosome is a ribonucleoprotein complex that removes introns from pre-mRNA, joins exons, and produces mature mRNA. Pathogenic variants in genes that code for spliceosome RNAs and proteins cause RNA mis-splicing and spliceosomopathies. Splicing defects during nervous system development upend the tightly controlled neurodevelopmental process, leading to neurodevelopmental disorders (NDDs). Despite the fact that the spliceosome is expressed in every cell, not all spliceosomopathies present as NDDs; spliceosomopathies are often tissue-specific in that a variant has a greater impact on certain cell lineages or cell types. Here we discuss spliceosomopathies whose presentations include NDDs and focus on spliceosome-coding genes.
{"title":"Spliceosome complex and neurodevelopmental disorders","authors":"Hannah M Deutsch , Yuanquan Song , Dong Li","doi":"10.1016/j.gde.2025.102358","DOIUrl":"10.1016/j.gde.2025.102358","url":null,"abstract":"<div><div>Neurodevelopment requires complex spatiotemporal expression, which heavily relies on proper RNA splicing. The spliceosome is a ribonucleoprotein complex that removes introns from pre-mRNA, joins exons, and produces mature mRNA. Pathogenic variants in genes that code for spliceosome RNAs and proteins cause RNA mis-splicing and spliceosomopathies. Splicing defects during nervous system development upend the tightly controlled neurodevelopmental process, leading to neurodevelopmental disorders (NDDs). Despite the fact that the spliceosome is expressed in every cell, not all spliceosomopathies present as NDDs; spliceosomopathies are often tissue-specific in that a variant has a greater impact on certain cell lineages or cell types. Here we discuss spliceosomopathies whose presentations include NDDs and focus on spliceosome-coding genes.</div></div>","PeriodicalId":50606,"journal":{"name":"Current Opinion in Genetics & Development","volume":"93 ","pages":"Article 102358"},"PeriodicalIF":3.7,"publicationDate":"2025-05-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144069178","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-05-06DOI: 10.1016/j.gde.2025.102352
Andreas Blaha , Alexander Schleiffer , Andrea Pauli
Fertilization — the process during which sperm and egg find each other, bind and eventually fuse — marks the beginning of a new individual. Research over the past years in vertebrates has shed new light on conserved and divergent molecular regulators that mediate the formation of the fertilization synapse, the close apposition of the two plasma membranes before fusion. Here, we review the known proteins that are required for sperm–egg interaction in mammals and fish from a phylogenetic perspective. While some sperm factors are only conserved in vertebrates and share phylogenetic and structural features, others have a longer evolutionary history. In contrast, the egg factors have changed even within vertebrates despite recognizing the preserved sperm machinery. Future functional work on these factors will be essential to understand the fusion mechanism of vertebrate sperm and egg.
{"title":"Conservation and divergence of the molecular regulators of the vertebrate fertilization synapse","authors":"Andreas Blaha , Alexander Schleiffer , Andrea Pauli","doi":"10.1016/j.gde.2025.102352","DOIUrl":"10.1016/j.gde.2025.102352","url":null,"abstract":"<div><div>Fertilization — the process during which sperm and egg find each other, bind and eventually fuse — marks the beginning of a new individual. Research over the past years in vertebrates has shed new light on conserved and divergent molecular regulators that mediate the formation of the fertilization synapse, the close apposition of the two plasma membranes before fusion. Here, we review the known proteins that are required for sperm–egg interaction in mammals and fish from a phylogenetic perspective. While some sperm factors are only conserved in vertebrates and share phylogenetic and structural features, others have a longer evolutionary history. In contrast, the egg factors have changed even within vertebrates despite recognizing the preserved sperm machinery. Future functional work on these factors will be essential to understand the fusion mechanism of vertebrate sperm and egg.</div></div>","PeriodicalId":50606,"journal":{"name":"Current Opinion in Genetics & Development","volume":"93 ","pages":"Article 102352"},"PeriodicalIF":3.7,"publicationDate":"2025-05-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143912173","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-05-05DOI: 10.1016/j.gde.2025.102354
Stephen Maxwell Scalf, Qiao Wu, Shangqin Guo
In the post-Yamanaka era, the rolling balls on Waddington’s hilly landscape not only roll downward, but also go upward or sideways. This new-found mobility implies that the tantalizing somatic cell plasticity fueling regeneration, once only known to planarians and newts, might be sparking in the cells of mice and humans, if only we knew how to fully unlock it. The hope for ultimate regeneration was made even more tangible by the observations that partial reprogramming by the Yamanaka factors reverses many hallmarks of aging [76], even though the underlying mechanism remains unclear. We intend to revisit the milestones in the evolving understanding of cell fate plasticity and glean molecular insights from an unusual somatic cell state, the privileged cell state that reprograms in a manner defying the stochastic model. We synthesize our view of the molecular underpinning of cell fate plasticity, from which we speculate how to harness it for regeneration and rejuvenation. We propose that senescence, aging and malignancy represent distinct cell states with definable biochemical and biophysical parameters.
{"title":"Molecular basis of cell fate plasticity — insights from the privileged cells","authors":"Stephen Maxwell Scalf, Qiao Wu, Shangqin Guo","doi":"10.1016/j.gde.2025.102354","DOIUrl":"10.1016/j.gde.2025.102354","url":null,"abstract":"<div><div>In the post-Yamanaka era, the rolling balls on Waddington’s hilly landscape not only roll downward, but also go upward or sideways. This new-found mobility implies that the tantalizing somatic cell plasticity fueling regeneration, once only known to planarians and newts, might be sparking in the cells of mice and humans, if only we knew how to fully unlock it. The hope for ultimate regeneration was made even more tangible by the observations that partial reprogramming by the Yamanaka factors reverses many hallmarks of aging [76], even though the underlying mechanism remains unclear. We intend to revisit the milestones in the evolving understanding of cell fate plasticity and glean molecular insights from an unusual somatic cell state, the privileged cell state that reprograms in a manner defying the stochastic model. We synthesize our view of the molecular underpinning of cell fate plasticity, from which we speculate how to harness it for regeneration and rejuvenation. We propose that senescence, aging and malignancy represent distinct cell states with definable biochemical and biophysical parameters.</div></div>","PeriodicalId":50606,"journal":{"name":"Current Opinion in Genetics & Development","volume":"93 ","pages":"Article 102354"},"PeriodicalIF":3.7,"publicationDate":"2025-05-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143906682","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-04-30DOI: 10.1016/j.gde.2025.102353
Amelie A Raz , Yukiko M Yamashita
Adult stem cells maintain tissue homeostasis through the production of differentiating cells. Considerable recent work has identified that stem cells themselves are replaceable through the process of dedifferentiation. The capacity and mechanisms of dedifferentiation vary widely among species and organ contexts. However, some core features are commonly present. In this review, we summarize ‘hallmarks’ of dedifferentiation, including mechanisms for maintenance of potency, sensation of loss, and migration, and review the current understanding of dedifferentiation as a true replacement mechanism.
{"title":"Rewinding the clock: mechanisms of dedifferentiation","authors":"Amelie A Raz , Yukiko M Yamashita","doi":"10.1016/j.gde.2025.102353","DOIUrl":"10.1016/j.gde.2025.102353","url":null,"abstract":"<div><div>Adult stem cells maintain tissue homeostasis through the production of differentiating cells. Considerable recent work has identified that stem cells themselves are replaceable through the process of dedifferentiation. The capacity and mechanisms of dedifferentiation vary widely among species and organ contexts. However, some core features are commonly present. In this review, we summarize ‘hallmarks’ of dedifferentiation, including mechanisms for maintenance of potency, sensation of loss, and migration, and review the current understanding of dedifferentiation as a true replacement mechanism.</div></div>","PeriodicalId":50606,"journal":{"name":"Current Opinion in Genetics & Development","volume":"93 ","pages":"Article 102353"},"PeriodicalIF":3.7,"publicationDate":"2025-04-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143890918","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-04-30DOI: 10.1016/j.gde.2025.102351
Melissa T Adams, Heinrich Jasper, Lluc Mosteiro
Partial reprogramming achieved by the transient expression of the transcription factors (TFs) Oct4, Sox2, Klf4 and C-Myc (abbreviated OSKM) can erase aging and damage features in cells, leading to increased healthspan, lifespan and tissue regeneration. Recent reports suggest that the mechanisms of partial reprogramming may share some similarities with natural dedifferentiation and regeneration. Both processes appear to involve the transient repression of somatic identity through the sequestration of somatic identity TFs to noncanonical sites, which are opened by the high expression of pioneer TFs, leading to transient dedifferentiation into a fetal-like state. Here, we review the reported benefits of partial reprogramming on tissue regeneration and propose a common mechanism of epigenetic remodeling with natural regeneration after tissue injury.
{"title":"Unlocking regeneration: how partial reprogramming resembles tissue healing","authors":"Melissa T Adams, Heinrich Jasper, Lluc Mosteiro","doi":"10.1016/j.gde.2025.102351","DOIUrl":"10.1016/j.gde.2025.102351","url":null,"abstract":"<div><div>Partial reprogramming achieved by the transient expression of the transcription factors (TFs) Oct4, Sox2, Klf4 and C-Myc (abbreviated OSKM) can erase aging and damage features in cells, leading to increased healthspan, lifespan and tissue regeneration. Recent reports suggest that the mechanisms of partial reprogramming may share some similarities with natural dedifferentiation and regeneration. Both processes appear to involve the transient repression of somatic identity through the sequestration of somatic identity TFs to noncanonical sites, which are opened by the high expression of pioneer TFs, leading to transient dedifferentiation into a fetal-like state. Here, we review the reported benefits of partial reprogramming on tissue regeneration and propose a common mechanism of epigenetic remodeling with natural regeneration after tissue injury.</div></div>","PeriodicalId":50606,"journal":{"name":"Current Opinion in Genetics & Development","volume":"93 ","pages":"Article 102351"},"PeriodicalIF":3.7,"publicationDate":"2025-04-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143890916","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-04-29DOI: 10.1016/j.gde.2025.102350
Yingwo Sun, Marc Vermulst
At first glance, biological systems appear to operate with remarkable precision and order. Yet, closer examination reveals that this perfection is an illusion, biological processes are inherently prone to errors. Here, we describe recent evidence that indicates that errors that occur during transcription play an important role in neurological diseases. These errors, though transient, can have lasting consequences when they generate mutant proteins with amyloid or prion-like properties. Such proteins can seed aggregation cascades, converting wild-type counterparts into misfolded conformations, ultimately leading to toxic deposits seen in diseases like Alzheimer’s and amyotrophic lateral sclerosis. These observations help to paint a fuller picture of the origins of neurodegenerative diseases in aging humans and suggest a unified mechanism by which they may arise.
{"title":"The hidden costs of imperfection: transcription errors in protein aggregation diseases","authors":"Yingwo Sun, Marc Vermulst","doi":"10.1016/j.gde.2025.102350","DOIUrl":"10.1016/j.gde.2025.102350","url":null,"abstract":"<div><div>At first glance, biological systems appear to operate with remarkable precision and order. Yet, closer examination reveals that this perfection is an illusion, biological processes are inherently prone to errors. Here, we describe recent evidence that indicates that errors that occur during transcription play an important role in neurological diseases. These errors, though transient, can have lasting consequences when they generate mutant proteins with amyloid or prion-like properties. Such proteins can seed aggregation cascades, converting wild-type counterparts into misfolded conformations, ultimately leading to toxic deposits seen in diseases like Alzheimer’s and amyotrophic lateral sclerosis. These observations help to paint a fuller picture of the origins of neurodegenerative diseases in aging humans and suggest a unified mechanism by which they may arise.</div></div>","PeriodicalId":50606,"journal":{"name":"Current Opinion in Genetics & Development","volume":"93 ","pages":"Article 102350"},"PeriodicalIF":3.7,"publicationDate":"2025-04-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143881751","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-04-25DOI: 10.1016/j.gde.2025.102348
Sung-Ya Lin , Mia T Levine
Telomeres are essential nucleoprotein structures that preserve our terminal DNA sequence and protect chromosome ends from fusion. Our vast knowledge of telomeres comes almost entirely from studies of healthy and diseased somatic cells. However, building evidence suggests that the molecules and mechanisms required for telomere integrity in somatic cells are insufficient to preserve telomere integrity during the sperm-to-embryo transition. Here, we review this growing body of work on telomere ‘paternal effects’, wherein zygotic telomere integrity is determined not by the genotype of the zygote but instead by the genotype of the father. Direct inheritance of sperm-specific proteins establishes paternal telomere epigenetic identity, while direct inheritance of sperm telomere length contributes to telomere length inheritance. Together, these investigations of telomere integrity through the sperm-to-embryo transition reveal potent paternal effects on zygotic telomere functions, with implications for human infertility.
{"title":"Paternal effects on telomere integrity during the sperm-to-embryo transition","authors":"Sung-Ya Lin , Mia T Levine","doi":"10.1016/j.gde.2025.102348","DOIUrl":"10.1016/j.gde.2025.102348","url":null,"abstract":"<div><div>Telomeres are essential nucleoprotein structures that preserve our terminal DNA sequence and protect chromosome ends from fusion. Our vast knowledge of telomeres comes almost entirely from studies of healthy and diseased somatic cells. However, building evidence suggests that the molecules and mechanisms required for telomere integrity in somatic cells are insufficient to preserve telomere integrity during the sperm-to-embryo transition. Here, we review this growing body of work on telomere ‘paternal effects’, wherein zygotic telomere integrity is determined not by the genotype of the zygote but instead by the genotype of the father. Direct inheritance of sperm-specific proteins establishes paternal telomere epigenetic identity, while direct inheritance of sperm telomere length contributes to telomere length inheritance. Together, these investigations of telomere integrity through the sperm-to-embryo transition reveal potent paternal effects on zygotic telomere functions, with implications for human infertility.</div></div>","PeriodicalId":50606,"journal":{"name":"Current Opinion in Genetics & Development","volume":"93 ","pages":"Article 102348"},"PeriodicalIF":3.7,"publicationDate":"2025-04-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143868698","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-04-16DOI: 10.1016/j.gde.2025.102349
Stefanie Williams, Robin Scott Hawley
The synaptonemal complex (SC) is structurally conserved across eukaryotes and is essential for a proper progression of meiosis. Despite this conservation, SC protein sequences diverge drastically. In this review, we explore findings on SC protein evolution, highlighting key differences and commonalities among lineages like the Caenorhabditis and the Drosophila genera. We further explore known cases where the SC and its proteins adopt novel functional roles and discuss why knowledge of these cases could be important for the study of canonical SC biology. The existing studies demonstrate that work on the evolutionary biology of SC proteins and functional studies in more diverse meiotic research organisms should play a major role in aiding our understanding of SC structure and functions.
{"title":"From conservation to adaptation: understanding the synaptonemal complex’s evolutionary dynamics","authors":"Stefanie Williams, Robin Scott Hawley","doi":"10.1016/j.gde.2025.102349","DOIUrl":"10.1016/j.gde.2025.102349","url":null,"abstract":"<div><div>The synaptonemal complex (SC) is structurally conserved across eukaryotes and is essential for a proper progression of meiosis. Despite this conservation, SC protein sequences diverge drastically. In this review, we explore findings on SC protein evolution, highlighting key differences and commonalities among lineages like the <em>Caenorhabditis</em> and the <em>Drosophila</em> genera. We further explore known cases where the SC and its proteins adopt novel functional roles and discuss why knowledge of these cases could be important for the study of canonical SC biology. The existing studies demonstrate that work on the evolutionary biology of SC proteins and functional studies in more diverse meiotic research organisms should play a major role in aiding our understanding of SC structure and functions.</div></div>","PeriodicalId":50606,"journal":{"name":"Current Opinion in Genetics & Development","volume":"93 ","pages":"Article 102349"},"PeriodicalIF":3.7,"publicationDate":"2025-04-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143843881","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
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