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

 描述（由申请人提供）：在整个发育过程中，诱导生长因子被粘附性地用于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少量的信号产生，但它需要发育中的细胞随着时间的推移差异地解释生长因子的活动。我们一直在研究骨形态发生蛋白（BMPs）粘附性地用于在发育中的脊髓中建立背侧回路的机制。这些研究将直接阐明我们在损伤后重建脊髓的能力，以及我们对缺陷导致的先天性疾病的理解。 在BMP信号通路中。BMP从顶板（RP）起作用以首先图案化周围组织，然后向远离背中线延伸的轴突提供引导信息。令人惊讶的是，骨形成蛋白诱导细胞命运的模式仍然不清楚：尽管人们广泛认为它们作为形态发生素来形成背侧脊髓，但这种模式尚未得到明确证实。相反，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具有不同的影响。我们将在目标1中解决BMP是否定量地作为形态发生剂或更定性地指定细胞命运。在目标2中，我们将确定BMPs的不同活性如何被背侧中间神经元（IN）翻译，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。两种I型BMP受体BmprIa和BmprIb共同的冗余活性允许它们通过激活典型的Smad中间体Smad 5来介导背侧细胞命运的规范。相反，BmprIb通过激活Lim激酶1（Limk 1）/cofilin途径和（pupil）Smad 1独特地介导BMP的引导活性。我们将评估两个机制的基础，Smad 1，Smad 5和Limk 1的差异激活的I型BmMPs和不同的机制，Smad 5和Smad 1，然后分别调节细胞命运的规范和轴突延伸的控制在以下目标：目的1：确定的模式，多个骨形态发生蛋白直接细胞的命运在背侧脊髓。假设：不同的骨形态发生蛋白定性分化祖神经元到不同的背侧IN群体。目的2：确定脊髓背侧神经元翻译BMP差异活性的机制。假设：背侧脊髓中BMP的不同活性通过不同的受体活化模式和/或特定第二信使的作用来翻译。

 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.