Specification of neuronal identities by feedforward combinatorial coding.
Specification of neuronal identities by feedforward combinatorial coding.
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DOI：
10.1371/journal.pbio.0050037
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发表时间：
2007-02
期刊：
影响因子：
9.8
通讯作者：
Thor S
中科院分区：
文献类型：
--
作者：
Baumgardt M;Miguel-Aliaga I;Karlsson D;Ekman H;Thor S
神经元的特化通常被视为一个多步骤的过程：早期的监管机构赋予广泛的神经元的身份，其次是组合代码指定特定亚型的神经元特性。然而，目前还不清楚是否早期监管机构重新部署在亚型特异性组合代码，以及是否早期图案化事件的行为，以限制有丝分裂后细胞的发育潜力。在这里，我们使用两个谱系相关的肽能神经元在果蝇腹神经索的差异肽能命运，以显示如何，在前馈机制，早期的决定因素成为关键球员在后来的组合代码。在成神经细胞5-6的后代中有两个肽能神经元：一个表达FMRFamide，另一个表达Nplp 1和多巴胺受体DopR。我们显示HLH基因collier在三个不同的水平上发挥作用，以逐步限制5-6谱系中的神经元身份。在最后一步，collier是区分两个部分重叠的组合代码的关键组合因子，所述组合代码定义FMRFamide与Nplp 1/DopR身份。错误表达实验表明，这两种密码子都能激活大量神经元中神经肽基因的表达。尽管它们的组成部分重叠，但我们发现这些密码非常特异，每个密码只激活适当的神经肽基因。这些结果表明，有限数量的监管机构可能构成一个强有力的组合代码，决定独特的神经元细胞的命运，这样的代码显示出令人惊讶的忽视许多全球性的指导性线索。通过研究果蝇腹神经索中两个谱系相关神经元的差异肽能命运，作者提供了更深入的见解，了解在前馈机制中，早期发育决定因素如何成为后来定义细胞身份的组合代码的关键参与者。神经系统包含了数量惊人的不同类型的细胞，在哺乳动物中可能多达10，000种，远远超过许多动物物种中的调节基因。在过去的十年中，在许多系统中的细胞命运的决定因素的研究支持的结论是，细胞的命运是不是由任何一个调控基因，但从几个监管机构的组合作用的结果。然而，关于这类守则的性质仍有许多问题。例如，不知道这些守则有多复杂，也不知道它们是如何制定的。也不清楚他们的行动是否受到限制，或者他们的行为是否超出了正常范围。为了解决这些悬而未决的问题，我们使用了两个独特的果蝇神经元的子集，可识别的两种不同的神经肽基因的特异性表达。我们已经确定了两个部分重叠和相对简单的代码，由四到七个监管机构的行为，以指定这两种细胞类型。有趣的是，规范是以前馈方式实现的，A激活B，然后A/B激活C，A/B/C激活D。每一种密码都有惊人的效力，可以异位激活多种神经元中的神经肽基因表达，而对许多早期的模式化事件却有着惊人的忽视。
Neuronal specification is often seen as a multistep process: earlier regulators confer broad neuronal identity and are followed by combinatorial codes specifying neuronal properties unique to specific subtypes. However, it is still unclear whether early regulators are re-deployed in subtype-specific combinatorial codes, and whether early patterning events act to restrict the developmental potential of postmitotic cells. Here, we use the differential peptidergic fate of two lineage-related peptidergic neurons in the Drosophila ventral nerve cord to show how, in a feedforward mechanism, earlier determinants become critical players in later combinatorial codes. Amongst the progeny of neuroblast 5–6 are two peptidergic neurons: one expresses FMRFamide and the other one expresses Nplp1 and the dopamine receptor DopR. We show the HLH gene collier functions at three different levels to progressively restrict neuronal identity in the 5–6 lineage. At the final step, collier is the critical combinatorial factor that differentiates two partially overlapping combinatorial codes that define FMRFamide versus Nplp1/DopR identity. Misexpression experiments reveal that both codes can activate neuropeptide gene expression in vast numbers of neurons. Despite their partially overlapping composition, we find that the codes are remarkably specific, with each code activating only the proper neuropeptide gene. These results indicate that a limited number of regulators may constitute a potent combinatorial code that dictates unique neuronal cell fate, and that such codes show a surprising disregard for many global instructive cues. By studying the differential peptidergic fate of two lineage-related neurons in theDrosophila ventral nerve cord, the authors provide deeper insights into how, in a feedforward mechanism, earlier developmental determinants become critical players in later combinatorial codes defining cell identity. The nervous system contains a daunting number of different cell types, perhaps as many as 10,000 in mammals, far outnumbering regulatory genes in many animal species. Studies of the determinants of cell fate in many systems during the last decade have supported the conclusion that cell fate is not determined by any one regulatory gene, but results from the combinatorial action of several regulators. Many questions about the nature of such codes, however, remain. It is not known, for example, how complex such codes are or how they are established. It is also unclear whether they are confined in their action or if they act outside of their normal context. To address these outstanding issues, we have used two unique subsets of Drosophila neurons, identifiable by their specific expression of two different neuropeptide genes. We have identified two partially overlapping and relatively simple codes, consisting of four to seven regulators that act to specify these two cell types. Intriguingly, specification is achieved in a feedforward manner such that A activates B, followed by A/B activating C, and A/B/C activating D. Each code is surprisingly potent, and can ectopically activate neuropeptide gene expression in a variety of neurons, with a surprising disregard for many early patterning events.
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