Información - Developmental biology - # Timing of Blastomere Polarization and its Impact on Cell Fate Allocation in Mouse Embryos

Asynchronous Polarization in Mouse Embryos Leads to Heterogeneity in Cell Fate Specification

Q: How do the differences in polarization timing and cell fate bias between early and late polarizing blastomeres impact the overall development and fitness of the embryo?

The differences in polarization timing and cell fate bias between early and late polarizing blastomeres play a crucial role in the overall development and fitness of the embryo. Early polarizing blastomeres exhibit distinct molecular and morphological characteristics that predispose them towards the trophectoderm (TE) lineage, which is essential for forming the placenta. This early polarization is associated with higher levels of CDX2 expression, a key transcription factor that drives TE specification. Consequently, early polarizing cells are more likely to undergo symmetric cell divisions, leading to a greater number of TE progeny. In contrast, late polarizing blastomeres tend to retain pluripotency markers and are biased towards the inner cell mass (ICM) lineage, which gives rise to the embryo proper. This asynchronous polarization results in a heterogeneous population of cells within the embryo, which is vital for establishing the correct balance between embryonic and extra-embryonic tissues. The fitness of the embryo is enhanced by this heterogeneity, as it allows for a more robust response to environmental cues and developmental signals, ultimately ensuring successful implantation and development. Moreover, the timing of polarization influences the spatial organization of cells within the embryo, which is critical for proper morphogenesis. The early polarizing cells, by forming the outer layer, contribute to the structural integrity of the blastocyst, while the late polarizing cells, positioned internally, maintain the potential for further differentiation. This balance is essential for the embryo's viability and successful transition to later developmental stages.

Q: What other molecular factors, beyond CARM1 and BAF155, might contribute to the asynchronous polarization and lineage biases observed in the 8-cell stage embryo?

In addition to CARM1 and BAF155, several other molecular factors may contribute to the asynchronous polarization and lineage biases observed in the 8-cell stage embryo. Key among these are the RhoA signaling pathway and the transcription factors TEAD4 and TFAP2C. RhoA is known to mediate the actomyosin network's activation, which is essential for the formation of the apical domain during polarization. The inhibition of RhoA has been shown to abolish polarization, indicating its critical role in this process. Furthermore, the Hippo signaling pathway, which regulates cell growth and differentiation, is also implicated in the polarization process. The apical domain's formation leads to the inactivation of Hippo signaling, promoting the nuclear translocation of YAP and subsequent upregulation of TE lineage determinants like CDX2. This interplay between the Hippo pathway and apical domain formation is crucial for establishing the lineage biases observed in early and late polarizing blastomeres. Other potential factors include the expression of specific cell adhesion molecules and cytoskeletal components that influence cell shape and intercellular interactions. For instance, keratin filaments have been shown to stabilize the apical domain and may play a role in the inheritance of polarization during cell division. Additionally, epigenetic modifications and the expression of other methyltransferases or chromatin remodelers could further modulate the timing of polarization and the subsequent lineage decisions.

Q: Could the principles of asynchronous polarization and its link to cell fate heterogeneity observed in the mouse embryo apply to other mammalian species, and what implications might this have for understanding early human development?

The principles of asynchronous polarization and the associated cell fate heterogeneity observed in the mouse embryo are likely applicable to other mammalian species, including humans. Similar mechanisms of early embryonic development, including the segregation of cell lineages and the establishment of polarity, are conserved across mammals. For instance, studies have shown that human pre-implantation embryos also exhibit variability in cell division timing and polarization, suggesting that these processes may influence lineage specification in a comparable manner. Understanding these principles in the context of human development has significant implications. The insights gained from mouse models can inform our understanding of human embryogenesis, particularly regarding the establishment of the blastocyst and the subsequent implantation process. Asynchronous polarization may contribute to the variability observed in human embryos, which could affect implantation success rates and overall reproductive outcomes. Moreover, the link between early polarization and cell fate decisions may provide a framework for investigating developmental disorders and infertility issues. By elucidating the molecular mechanisms underlying these processes, researchers could develop targeted interventions to improve embryo viability and enhance reproductive technologies, such as in vitro fertilization (IVF). Overall, the study of asynchronous polarization in mouse embryos offers valuable insights that could translate to better understanding and management of early human development.

Conceptos Básicos

Blastomeres in the mouse embryo polarize asynchronously, with some cells polarizing earlier than others, and this timing of polarization influences their subsequent cell fate specification.

Resumen

The study investigates the timing of blastomere polarization during the 8-cell stage of mouse embryo development and its impact on cell fate specification. The authors find that polarization is an asynchronous process, with some blastomeres polarizing earlier than others, before the embryo compacts.

Early polarizing blastomeres exhibit distinct features compared to late polarizing ones:

They have a closer nucleus-cortex distance and a larger apical domain size.
They show earlier upregulation of the trophectoderm (TE) lineage marker CDX2.
They are biased towards symmetric cell divisions, which leads to a higher contribution to the TE lineage.

The authors link this asynchronous polarization to earlier heterogeneities in the embryo, specifically lower activity of the arginine methyltransferase CARM1 and higher levels of its target BAF155. Reducing CARM1 activity or increasing BAF155 levels promotes early polarization, suggesting a mechanistic connection between 4-cell stage asymmetries and 8-cell stage polarization timing.

These findings provide insights into how early developmental heterogeneities can influence the first lineage segregation event in the mouse embryo, with implications for understanding the regulation of cell fate decisions.

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biorxiv.org

Estadísticas

The blastomeres polarizing early have a significantly larger apical domain size compared to late polarizing blastomeres.
Early polarizing blastomeres have a significantly smaller apical-nucleus distance compared to late polarizing blastomeres.
71.7% of early polarizing blastomeres divide symmetrically, compared to only 38.7% of late polarizing blastomeres.
82.8% of cells arising from early polarizing blastomeres contribute to the trophectoderm lineage, compared to 68.3% from late polarizing blastomeres.

Citas

"Blastomeres polarizing at the early and late 8-cell stage have distinct molecular and morphological properties that direct their following lineage specification, with early polarizing cells being biased towards producing the TE lineage."
"Blastomeres with the lowest CARM1 activity have the lowest methylation of CARM1 targets and contribute preferentially to TE, whereas cells with higher CARM1 becoming biased towards ICM."
"Decreased CARM1 activity and elevated BAF155 expression can enable blastomeres to polarize early."

Ideas clave extraídas de

Asynchronous mouse embryo polarization leads to heterogeneity in cell fate specification

by Lamba,A., Zh... a las www.biorxiv.org 07-26-2024

https://www.biorxiv.org/content/10.1101/2024.07.26.605266v1

Consultas más profundas

How do the differences in polarization timing and cell fate bias between early and late polarizing blastomeres impact the overall development and fitness of the embryo?

The differences in polarization timing and cell fate bias between early and late polarizing blastomeres play a crucial role in the overall development and fitness of the embryo. Early polarizing blastomeres exhibit distinct molecular and morphological characteristics that predispose them towards the trophectoderm (TE) lineage, which is essential for forming the placenta. This early polarization is associated with higher levels of CDX2 expression, a key transcription factor that drives TE specification. Consequently, early polarizing cells are more likely to undergo symmetric cell divisions, leading to a greater number of TE progeny.
In contrast, late polarizing blastomeres tend to retain pluripotency markers and are biased towards the inner cell mass (ICM) lineage, which gives rise to the embryo proper. This asynchronous polarization results in a heterogeneous population of cells within the embryo, which is vital for establishing the correct balance between embryonic and extra-embryonic tissues. The fitness of the embryo is enhanced by this heterogeneity, as it allows for a more robust response to environmental cues and developmental signals, ultimately ensuring successful implantation and development.
Moreover, the timing of polarization influences the spatial organization of cells within the embryo, which is critical for proper morphogenesis. The early polarizing cells, by forming the outer layer, contribute to the structural integrity of the blastocyst, while the late polarizing cells, positioned internally, maintain the potential for further differentiation. This balance is essential for the embryo's viability and successful transition to later developmental stages.

What other molecular factors, beyond CARM1 and BAF155, might contribute to the asynchronous polarization and lineage biases observed in the 8-cell stage embryo?

In addition to CARM1 and BAF155, several other molecular factors may contribute to the asynchronous polarization and lineage biases observed in the 8-cell stage embryo. Key among these are the RhoA signaling pathway and the transcription factors TEAD4 and TFAP2C. RhoA is known to mediate the actomyosin network's activation, which is essential for the formation of the apical domain during polarization. The inhibition of RhoA has been shown to abolish polarization, indicating its critical role in this process.
Furthermore, the Hippo signaling pathway, which regulates cell growth and differentiation, is also implicated in the polarization process. The apical domain's formation leads to the inactivation of Hippo signaling, promoting the nuclear translocation of YAP and subsequent upregulation of TE lineage determinants like CDX2. This interplay between the Hippo pathway and apical domain formation is crucial for establishing the lineage biases observed in early and late polarizing blastomeres.
Other potential factors include the expression of specific cell adhesion molecules and cytoskeletal components that influence cell shape and intercellular interactions. For instance, keratin filaments have been shown to stabilize the apical domain and may play a role in the inheritance of polarization during cell division. Additionally, epigenetic modifications and the expression of other methyltransferases or chromatin remodelers could further modulate the timing of polarization and the subsequent lineage decisions.

Could the principles of asynchronous polarization and its link to cell fate heterogeneity observed in the mouse embryo apply to other mammalian species, and what implications might this have for understanding early human development?

The principles of asynchronous polarization and the associated cell fate heterogeneity observed in the mouse embryo are likely applicable to other mammalian species, including humans. Similar mechanisms of early embryonic development, including the segregation of cell lineages and the establishment of polarity, are conserved across mammals. For instance, studies have shown that human pre-implantation embryos also exhibit variability in cell division timing and polarization, suggesting that these processes may influence lineage specification in a comparable manner.
Understanding these principles in the context of human development has significant implications. The insights gained from mouse models can inform our understanding of human embryogenesis, particularly regarding the establishment of the blastocyst and the subsequent implantation process. Asynchronous polarization may contribute to the variability observed in human embryos, which could affect implantation success rates and overall reproductive outcomes.
Moreover, the link between early polarization and cell fate decisions may provide a framework for investigating developmental disorders and infertility issues. By elucidating the molecular mechanisms underlying these processes, researchers could develop targeted interventions to improve embryo viability and enhance reproductive technologies, such as in vitro fertilization (IVF). Overall, the study of asynchronous polarization in mouse embryos offers valuable insights that could translate to better understanding and management of early human development.