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

骨形态发生蛋白在脊髓发育中的多种作用

基本信息

批准号：
8818195
负责人：
SAMANTHA J BUTLER
金额：
$ 32.99万
依托单位：
UNIVERSITY OF CALIFORNIA LOS ANGELES
依托单位国家：
美国
项目类别：
财政年份：
2014
资助国家：
美国
起止时间：
2014-09-01 至 2019-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8818195
关键词：
Address Axon BMP4 BMP5 gene BMP6 gene BMP7 gene Biological Assay Bone Morphogenetic Proteins Cell physiology Cells ChIP-seq Chickens Complex Development Disease Dorsal Electroporation Embryo Extracellular Domain Growth Factor In Vitro Individual Injury Interneurons Light Mediating Modeling Mus Neurons Organism Output Pathway interactions Pattern Phosphotransferases Population Process Receptor Activation Regulation Role Second Messenger Systems Signal Pathway Signal Transduction Specificity Spinal Spinal Cord Spinal cord damage Time Tissues To specify Translating axon guidance base bone morphogenetic protein receptor type I cell fate specification cofilin embryonic stem cell growth differentiation factor 7 in vivo member morphogens nerve stem cell neural circuit progenitor public health relevance receptor relating to nervous system second messenger tissue culture

项目摘要

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.