Introduction and Overview

• This paper explores how symmetry and asymmetry are established during embryonic development.
• Although animals often appear bilaterally symmetrical on the outside, their internal organs (such as the heart, liver, spleen, and gut) are arranged asymmetrically.
• The left-right (LR) axis is unique because there is no obvious external cue to distinguish left from right; yet, all normal individuals show the same internal asymmetry.
• The research investigates how the process of twinning can affect LR asymmetry and lead to laterality defects.

What is Left-Right Asymmetry?

• Vertebrates are externally symmetrical but internally, organs are positioned asymmetrically.
• This asymmetry is conserved across species, meaning most individuals share the same left-right pattern.
• Key definitions:
  • situs inversus: a condition where internal organs are mirror-reversed.
  • heterotaxia: partial or random reversal of organ placement.
  • chirality: a property where an object or system is not superimposable on its mirror image (like left and right hands).

Key Concepts and Definitions

• Symmetry in embryogenesis is a fundamental guide for building the body plan.
• The left-right axis is determined very early, often before any organs visibly form.
• This process is controlled by specific genes and signaling molecules.
  • Sonic Hedgehog (Shh): a signal protein initially expressed symmetrically, later confined to the left side.
  • Nodal: a gene activated on the left side that influences later asymmetric development.
  • PTC: a receptor for Shh, found on the left side.
  • Pitx2: a transcription factor induced by Nodal that helps specify left-sided development.
  • Activin and cAct-RIIa: molecules involved in early signaling, with activin expressed on the right to modulate gene expression.
  • cSnR: a gene expressed on the right side and suppressed on the left by Nodal.

The Molecular Left-Right Pathway (Step-by-Step)

• Step 1: Expression of activin begins on the right side of the embryonic node.
  • This is similar to adding a unique spice to only one side of a dish to create a distinct flavor.
• Step 2: Activin induces cAct-RIIa expression on the right and represses Shh there, confining Shh expression to the left side.
• Step 3: Left-sided Shh then triggers the expression of PTC and subsequently induces Nodal.
  • This acts as a clear signal telling cells “this is the left side.”
• Step 4: Nodal spreads its signal to a larger group of cells in the lateral plate mesoderm and induces Pitx2 on the left.
• Step 5: Meanwhile, cSnR is maintained on the right side, as Nodal suppresses it on the left.
• Together, these steps ensure that organs such as the heart and stomach develop on their correct sides. Any disruption can lead to laterality defects.

Models for Conjoined Twins and Laterality Defects

• Conjoined twins sometimes show defects in left-right asymmetry.
• Certain twin types (like parapagus and thoracopagus) are more likely to exhibit mirror-image organ placement or other asymmetry issues.
• Two main models are proposed:
  • Model 1: When two embryonic streaks grow in parallel, activin from one streak can inhibit Shh expression in the adjacent twin. This leads to a lack of Nodal signal and results in asymmetry defects.
  • Model 2: When two streaks form far apart and then converge, both initially express Shh normally, but later one twin may receive extra signals causing aberrant Nodal expression and mixed or mirror-image asymmetry.
• These models illustrate how the physical arrangement and timing during early development can affect organ placement in twins.

Chirality Issues in Non-Conjoined Twins

• Even twins that are not physically connected can display subtle mirror-image differences.
• Examples include:
  • Differences in hand preference (left- or right-handedness).
  • Variations in hair whorl direction.
  • Differences in tooth patterns.
  • Minor variations in eye and ear features.
• These subtle traits suggest that early cell divisions carry chiral information that influences later left-right asymmetry.

Conclusions and Implications

• The paper highlights the complex, finely tuned process of establishing left-right asymmetry during embryonic development.
• Key takeaways:
  • Left-right asymmetry is established by a cascade of genetic signals that determine organ positioning.
  • Minor disruptions in these early events can lead to significant laterality defects.
  • The physical arrangement during twinning can influence how these signals are distributed, sometimes causing defects.
  • These insights help us better understand congenital conditions related to organ placement and may lead to improved diagnostics and treatments.

引言和概述

• 本文探讨了胚胎发育过程中如何建立对称性与不对称性。
• 尽管动物在外部通常呈现双侧对称，但其内脏（如心脏、肝脏、脾脏和肠道）的排列却是不对称的。
• 左右轴的形成非常独特，因为没有明显的外部线索来区分左右，但所有正常个体都遵循相同的不对称模式。
• 研究重点在于双胞胎形成过程中，这一过程如何影响左右不对称，并可能导致器官排列缺陷。

什么是左右不对称？

• 脊椎动物在外部看似对称，但内部器官的位置却不相同。
• 这种不对称性在大多数物种中是保守的，意味着大多数个体遵循相同的左右模式。
• 关键定义：
  • 器官位置倒置（situs inversus）：内脏器官呈镜像排列。
  • 异位症（heterotaxia）：器官位置部分或随机倒置。
  • 手性（chirality）：指物体或系统与其镜像不重叠，就像左手和右手一样。

关键概念和定义

• 胚胎发育中的对称性是构建体型的重要原则。
• 左右轴在胚胎早期就被确定下来，通常在器官形成之前。
• 这一过程由特定的基因和信号分子控制：
  • 声波分子 (Shh)：一种信号蛋白，最初在胚胎节点中对称表达，后来局限于左侧。
  • Nodal：在左侧激活的基因，对后续不对称性起关键作用。
  • PTC：Shh的受体，出现在左侧。
  • Pitx2：由Nodal诱导的转录因子，有助于确定左侧发育。
  • Activin和cAct-RIIa：早期信号分子，其中activin在右侧表达，用以调控其他基因。
  • cSnR：在右侧表达的基因，在左侧受到Nodal抑制。

分子左右不对称途径（逐步解析）

• 第一步：在胚胎节点右侧表达activin。
  • 这类似于在菜的一边加入独特的调料，以制造不同的风味。
• 第二步：Activin诱导右侧cAct-RIIa的表达，同时抑制右侧的Shh表达，使Shh只在左侧表达。
• 第三步：左侧的Shh进一步诱导PTC的表达，并随后激活Nodal。
  • 这一过程相当于向细胞发出“这里是左侧”的明确信号。
• 第四步：Nodal信号扩散到更多外侧板细胞，并在左侧诱导Pitx2的表达。
• 第五步：同时，cSnR在右侧表达，而在左侧由于Nodal的作用而受到抑制。
• 这些步骤确保心脏、胃等器官在正确的一侧发育；任何早期的轻微干扰都可能导致不对称缺陷。

连体双胞胎与不对称缺陷的模型

• 连体双胞胎有时会表现出左右不对称的缺陷。
• 某些类型的双胞胎（如侧并型和胸并型）更容易出现器官镜像倒置或其他不对称问题。
• 论文提出了两种主要模型：
  • 模型1：当两个胚胎原条平行生长时，一侧的activin信号可能抑制相邻双胞胎中Shh的表达，导致Nodal信号缺失，从而引发不对称缺陷。
  • 模型2：当两个原条最初分开但在原肠形成过程中逐渐靠近时，虽然初期两者均有正常的Shh表达，但随后一方可能会因接收到额外信号而导致Nodal表达异常，从而产生部分或完全的镜像不对称。
• 这些模型说明了早期胚胎结构的空间排列和时间对器官定位的重要影响。

非连体双胞胎中的手性问题

• 即使是非连体双胞胎（早期分离的个体）也可能表现出微妙的镜像差异。
• 例如：
  • 左右手偏好存在差异；
  • 头发旋涡方向不同；
  • 牙齿排列模式存在差异；
  • 眼睛和耳朵等部位可能有细微差别。
• 这些现象提示早期细胞分裂中携带的手性信息可能影响左右不对称的形成。

结论与启示

• 论文强调了胚胎发育中左右不对称建立的复杂性和精细调控。
• 主要结论：
  • 左右不对称由一系列基因信号级联控制，决定器官的最终位置；
  • 早期胚胎事件中的轻微变化可能导致严重的不对称缺陷；
  • 双胞胎形成过程中胚胎结构的空间排列对不对称性具有重要影响；
  • 这些发现为理解胚胎发育和相关先天性器官排列异常提供了新的视角，有助于改进诊断和治疗方法。