Diverse roles of the Bone Morphogenetic Proteins in the developing spinal cord

 描述(由申请人提供)：诱导性生长因子在整个发育过程中反复使用，以指导一系列非凡的细胞命运和过程。这种信号的经济性意味着，复杂的生物体可以由相对较少的信号产生，但它需要发育中的细胞来区别解释随着时间的推移生长因子的活动。我们一直在研究骨形态发生蛋白(BMPs)反复用于在发育中的脊髓建立背侧回路的机制。这些研究将直接揭示我们在受伤后重建脊髓的能力，以及我们对由缺陷引起的先天性疾病的理解。 在BMP信号通路中。BMP从顶板(RP)起作用，首先形成周围组织的图案，然后向远离背中线的轴突提供指导信息。令人惊讶的是，BMP诱导细胞命运的方式仍然不清楚：尽管人们普遍认为BMP作为形态原作用于背侧脊髓，但这个模型还没有得到明确的证明。相反，在RP中存在许多BMP，我们的初步研究表明，它们对特定神经命运的诱导有不同的影响。在目标1中，我们将确定BMP是定量地作为形态成因，还是更定性地指定细胞命运。在目标2中，我们将确定背侧中间神经元(INS)如何翻译BMP的不同活性，从而导致不同的细胞命运和/或过程。我们以前的研究表明，背侧INS在受体和第二信使水平上解释BMPs的不同活动。I型BMP受体BmprIa和BmprIb共有的冗余活性允许它们通过激活典型的Smad中间体Smad5来调节背部细胞命运的指定。相反，BmprIb通过激活LIM激酶1(LIMK1)/cofilin通路和(推测)Smad1来唯一地介导BMP的导向活性。我们将评估Smad1、Smad5和LIMK1被I型Bmprs差异激活的机制基础，以及Smad5和Smad1随后分别差异调节细胞命运指定和控制轴突伸展的不同机制，目的如下：目的1：确定多个BMP控制脊髓背侧细胞命运的方式。假设：不同的BMP定性地将前体神经元分化为不同的背侧IN群体。目的：探讨脊髓背侧神经元翻译骨形态发生蛋白差异活性的机制(S)。假设：BMPs在背侧脊髓的不同活动是通过不同的受体激活模式和/或特定的第二信使的作用来翻译的。

 DESCRIPTION (provided by applicant): Inductive growth factors are used reiteratively throughout development to direct an extraordinary range of cellular fates and processes. This economy of signaling means that complex organisms can be generated by a relatively small number of signals, but it requires developing cells to differentially interpret the activities of growth factors over time. We have been studying the mechanisms by which the Bone Morphogenetic Proteins (BMPs) are used reiteratively to establish dorsal circuitry in the developing spinal cord. These studies will shed direct light both on our ability to rebuild the spinal cord after injury and our understanding of the congenital diseases that result from deficits in the BMP signaling pathway. The BMPs act from the roof plate (RP) to first pattern the surrounding tissue and then provide guidance information to axons extending away from the dorsal midline. Surprisingly, the mode by which the BMPs induce cell fate remains unclear: although it is widely assumed that they act as morphogens to pattern the dorsal spinal cord, this model has not been clearly demonstrated. Rather, there are many BMPs present in the RP and our preliminary studies suggest that they have distinct effects on the induction of particular neural fates. We will resolve whether the BMPs act quantitatively as morphogens or more qualitatively to specify cell fate in Aim 1. In Aim 2, we will determine how the distinct activitie of the BMPs are translated by dorsal interneurons (INs) to result in different cellular fates and/or processes. Our previous studies have suggested that dorsal INs interpret the distinct activities of the BMPs at both the receptor and second messenger level. A redundant activity common to both type I BMP receptors, BmprIa and BmprIb, permits them to mediate the specification of dorsal cell fates by activating the canonical Smad intermediate, Smad5. In contrast, BmprIb uniquely mediates the guidance activities of the BMPs, by activating the Lim kinase 1 (Limk1)/cofilin pathway and (putatively) Smad1. We will assess both the mechanistic basis by which Smad1, Smad5 and Limk1 are differentially activated by the type I Bmprs and the different mechanisms by which Smad5 and Smad1 then differentially respectively regulate cell fate specification and the control of axon extension in the following aims: Aim 1: Determine the mode by which multiple BMPs direct cell fate in the dorsal spinal cord. Hypothesis: Distinct BMPs qualitatively differentiate progenitor neurons into distinct dorsal IN populations. Aim 2: Determine the mechanism(s) by which dorsal spinal neurons translate the differential activities of the BMPs. Hypothesis: The distinct activities of the BMPs in the dorsal spinal cord are translated by distinct patterns of receptor activation and/or the action of specific second messengers.