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Rethinking the neural crest - a novel dynamic hypothesis of neural crest fate restriction

重新思考神经嵴——一种新的神经嵴命运限制的动态假说

基本信息

批准号：
BB/S015906/1
负责人：
Robert Kelsh
金额：
$ 124.02万
依托单位：
University of Bath
依托单位国家：
英国
项目类别：
Research Grant
财政年份：
2019
资助国家：
英国
起止时间：
2019 至无数据
项目状态：
已结题

来源：
https://gtr.ukri.org/projects?ref=BB%2FS015906%2F1
关键词：
Rethinking neural crest novel dynamic

项目摘要

All cell types in the body derive from stem or other precursor cells. These precursors are multipotent, having the flexibility to develop into any one of many types of working cells (e.g. neurons, blood or skin cells). A major problem in developmental biology is to understand how these flexible precursors make a specific choice of cell-type to adopt. The scale of the problem is illustrated by the fact that for one key exemplar, neural crest stem cells, there is still uncertainty about how the process works even after four decades of research - do fully multipotent cells 'jump' straight to a specific chosen fate, or do they go through a series of steps in which their options become more and more limited, until eventually they choose a single cell-type? These two models - Direct Fate Restriction (DFR) and Progressive Fate Restriction (PFR) - have each received support from different studies, but are conflicting. Although PFR is now the textbook view of neural crest development, a prominent paper studying mouse neural crest recently concluded firmly with a DFR interpretation. As a result of work done on an ongoing BBSRC grant studying neural crest stem cells in zebrafish embryos, we are proposing a revolutionary new view, which we believe reconciles these conflicts. We have been looking at the formation of pigment cell-types from the neural crest, as a model of neural crest development in general. Specifically, we have been looking at melanocytes (black pigment cells, well-known for their roles in skin and hair colour in humans, and giving rise to melanoma), and iridophores, a shiny silver cell-type that is prominent in most fishes. We see evidence for only some very broadly multipotent precursors, leading us to propose our novel Cyclical Fate Restriction model. We think that neural crest precursors are variable because they are highly dynamic, constantly changing. This view is consistent with, and reconciles, the conflicting data and interpretations in the field. Increasingly, stem cell biology is being explored using a mathematical modelling approach which has often given key insights into how they function. Surprisingly, perhaps, almost all this work has focused on 'binary choices', and so has ignored the possibilities of a DFR-type process. Even for PFR, modelling has not explored how binary choices might be interlinked to generate multiple diverse derivatives.In this project, we will test and explore our new Cyclical Fate Restriction model, using experimental studies and mathematical modelling to gain insight into how the process might work. A key experiment is to use a complementary technique to look at gene activity in thousands of neural crest cells, looking comprehensively at their cell-profiles so as to study the range of identifiable precursor states in the neural crest. We will then use a sensitive technique to look at such cell-types directly in the embryo. In parallel we will explore the mathematical basis for the three models, developing current models to describe PFR, and applying novel theoretical insights to stem cell biology to investigate the plausibility of both DFR and our novel Cyclical model. We will integrate the two approaches, experimentally investigating biological features relevant to the models, including direct assessment of the direction of change of progenitor cells, and quantitative investigation of the key fate specification signals in the neural crest.Together, these studies will test a revolutionary view of neural crest stem cell biology. Understanding these processes has implications well beyond the basic biology we are studying here. In particular, it is important in a medical context, in that this process of stem cells choosing between different cell-types is of fundamental importance to understanding the healthy body and how it goes wrong in ageing and in disease. It thus will shed light on the mechanisms underlying congenital diseases and cancer.

人体内的所有细胞类型都来自干细胞或其他前体细胞。这些前体是多能的，具有发展成多种工作细胞（如神经元、血液或皮肤细胞）中的任何一种的灵活性。发育生物学的一个主要问题是了解这些灵活的前体是如何对所采用的细胞类型做出特定选择的。对于神经嵴干细胞这一关键范例来说，即使经过40年的研究，这个过程如何运作仍然存在不确定性——完全多能细胞是直接“跳跃”到特定的选择命运，还是经过一系列的步骤，它们的选择越来越有限，直到最终选择一种单一的细胞类型？这两个模型-直接命运限制（DFR）和渐进命运限制(PFR) -各自得到了不同研究的支持，但相互矛盾。虽然PFR现在是神经嵴发育的教科书观点，但最近一篇研究小鼠神经嵴的著名论文坚定地得出了DFR解释。基于BBSRC对斑马鱼胚胎神经嵴干细胞的研究，我们提出了一种革命性的新观点，我们相信它可以调和这些矛盾。我们一直在研究神经嵴中色素细胞类型的形成，作为神经嵴发育的一般模型。具体来说，我们一直在研究黑素细胞（黑色色素细胞，因其在人类皮肤和头发颜色中的作用而闻名，并导致黑色素瘤的产生）和虹膜细胞，一种在大多数鱼类中都很突出的闪亮的银色细胞类型。我们只看到了一些非常广泛的多能前体的证据，这促使我们提出了新的周期性命运限制模型。我们认为神经嵴前体是可变的，因为它们是高度动态的，不断变化的。这一观点与该领域中相互矛盾的数据和解释是一致的，并加以调和。越来越多地，干细胞生物学正在使用数学建模方法进行探索，这种方法通常提供了对它们如何发挥作用的关键见解。也许令人惊讶的是，几乎所有这些工作都集中在“二元选择”上，因此忽略了dfr类型过程的可能性。即使对于PFR，建模也没有探索二元选择如何相互联系以产生多种不同的衍生品。在这个项目中，我们将测试和探索我们新的周期性命运限制模型，使用实验研究和数学模型来深入了解这个过程是如何工作的。一个关键的实验是使用一种互补技术来观察数千个神经嵴细胞的基因活性，全面观察它们的细胞谱，从而研究神经嵴中可识别的前体状态的范围。然后，我们将使用一种灵敏的技术直接在胚胎中观察这些细胞类型。同时，我们将探索这三种模型的数学基础，开发当前的模型来描述PFR，并将新的理论见解应用于干细胞生物学，以研究DFR和我们的新周期模型的合理性。我们将整合这两种方法，通过实验研究与模型相关的生物学特征，包括直接评估祖细胞的变化方向，以及定量研究神经嵴中关键的命运规范信号。总之，这些研究将测试神经嵴干细胞生物学的革命性观点。理解这些过程的意义远远超出了我们在这里学习的基础生物学。特别是在医学背景下，干细胞在不同细胞类型之间进行选择的过程对于理解健康的身体以及它在衰老和疾病中是如何出错的至关重要。因此，它将揭示先天性疾病和癌症的潜在机制。

项目成果

期刊论文数量（10）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Notch controls the cell cycle to define leader versus follower identities during collective cell migration.

Notch控制了细胞周期，以定义集体细胞迁移期间的领导者与追随者身份。

DOI：
10.7554/elife.73550
发表时间：
2022-04-19
期刊：
ELIFE
影响因子：
7.7
作者：
Alhashem, Zain;Feldner-Busztin, Dylan;Revell, Christopher;Portillo, Macarena Alvarez-Garcillan;Camargo-Sosa, Karen;Richardson, Joanna;Rocha, Manuel;Gauert, Anton;Corbeaux, Tatianna;Milanetto, Martina;Argenton, Francesco;Tiso, Natascia;Kelsh, Robert N.;Prince, Victoria E.;Bentley, Katie;Linker, Claudia
通讯作者：
Linker, Claudia

Cell Fate Decisions in the Neural Crest, from Pigment Cell to Neural Development.

从色素细胞到神经发育，神经rest中的细胞命运决定。