The proper development of the nervous system is dependent on a number of cellular processes occurring at the appropriate time and location. One such cellular process that is required for proper nervous system development is the appropriate localization and translation of certain mRNA transcripts. The localization of these transcripts is dependent on mRNA binding proteins, a class of molecules responsible for the transport, and in some cases, translation of their mRNA cargo. Zipcode binding protein 1 (ZBP1) is an mRNA binding protein that is responsible for the transport and regulates the translation of ?-actin mRNA. ?-actin is important for the development of the nervous system because it is one of the major structural proteins that composes the growth cone, the pathfinding structure of a developing neuron.
The aim of the current proposal is to determine how the loss of ZBP1 affects nervous system development and specifically, the growth cone. It is of great importance to study the function of ZBP1 because it is essential for appropriate gross development. The current proposal has two main goals: 1) to examine the role of ZBP1 in the regulation of axon outgrowth and guidance and 2) to examine the role of ZBP1 in the transport and translation of ?-actin mRNA. To determine the role of ZBP1 in these processes, lentiviral vector-mediated shRNA interference to ZBP1 will be employed, as well as a ZBP1 knockout mouse model. This proposal also uses innovative fluorescent proteins and reporters in primary neuronal cultures in order to achieve the above stated aims. It is essential to study the localization and translation of ?-actin mRNA because it encodes a structural protein that is required for proper growth cone motility and guidance, and therefore is required for the correct connectivity of the nervous system to be established. The long-term objective of this proposal is to gain an understanding of the basic mechanisms that are required for axon outgrowth and growth cone guidance, such as local translation of mRNA transcripts within the growth cone;this information will further our knowledge about the appropriate development of the nervous system as a whole. The development of the nervous system is a process during which neurons must find their way to and make connections with their appropriate targets. If this does not happen properly, a number of disease states may result. This proposal investigates the role of the protein ZBP1, which is responsible for transporting mRNA during development;the loss of this protein may result in inappropriate development of the nervous system and thus, a neurological disease state.
|Ceci, Marcello; Welshhans, Kristy; Ciotti, Maria Teresa et al. (2012) RACK1 is a ribosome scaffold protein for Ã½Ã½-actin mRNA/ZBP1 complex. PLoS One 7:e35034|
|Welshhans, Kristy; Bassell, Gary J (2011) Netrin-1-induced local Ã½Ã½-actin synthesis and growth cone guidance requires zipcode binding protein 1. J Neurosci 31:9800-13|
|Sasaki, Yukio; Welshhans, Kristy; Wen, Zhexing et al. (2010) Phosphorylation of zipcode binding protein 1 is required for brain-derived neurotrophic factor signaling of local beta-actin synthesis and growth cone turning. J Neurosci 30:9349-58|