The long-term goal of this application is to understand the molecular and cellular mechanisms that govern the migration of neuronal precursors (neuroblasts) in the postnatal mammalian forebrain. These precursors are generated in the forebrain subventricular zone (SVZ) and then migrate via the rostral migratory stream (RMS) to the olfactory bulb (OB) where they join existing circuitries and differentiate into interneurons. Proper migration and integration of newly generated neuroblasts into the OB is important for olfactory learning and plasticity, and, significantly, deficiencies in these processes have been linked to abnormal innate and social behavior. Importantly, neuroblasts are also capable of migrating to sites of injury in the brain, raising the possibility for their use in brain therapies Despite the importance of neuroblast migration, little is known about the molecular mechanisms that regulate this process. We recently uncovered that the DOCK180 family member DOCK7, an activator of Rac, is prominently expressed in neuroblasts in the forebrain of postnatal/adult mice, and importantly that it plays a critical role in neuroblast migration in the RMS. Furthermore, we found that DOCK7 interacts with the schizophrenia-associated ErbB4 tyrosine kinase receptor, which notably was shown to influence RMS neuroblast migration. These findings provide a unique entry point for studying the molecular basis of neuroblast migration in the postnatal forebrain. This application aims to further define DOCK7's role in migrating neuroblasts and identify the molecular pathways DOCK7 is integral to. Towards these goals, Aim 1 will further scrutinize the effects of DOCK7 depletion on the migratory behavior of neuroblasts by performing genetic and live cell imaging experiments. We will also determine the ensuing fate of DOCK7 depleted neuroblasts, taking advantage of a CreER transgenic mouse model and inducible RNAi technology.
Aim 2 will investigate mechanisms of DOCK7 regulation in migrating neuroblasts, with a particular focus on ErbB4, which we postulate is a key regulator of DOCK7 in neuroblast migration. We will test this hypothesis using molecular, genetic and biochemical approaches and will further define DOCK7 regulatory elements important for this interaction and DOCK7 function in neuroblasts. Finally, Aim 3 will characterize molecular mechanisms downstream of DOCK7 in migrating neuroblasts. Our preliminary data suggest that DOCK7 exerts its effects via both Rac-dependent and Rac-independent pathways, each influencing distinct cellular aspects of neuroblast migration. Hence, we will strive to delineate te Rac-mediated signaling pathway(s) involved and identify novel molecular interactions that mediate DOCK7's effects on neuroblast migration, using innovative genetic, molecular and cellular approaches. The proposed studies will provide novel insights into the mechanisms governing postnatal neuroblast migration. As such, they should shed light onto the signaling defects that underlie olfactory deficits and associated CNS disorders, and could aid in the development of novel therapeutic strategies to treat brain injury.

Public Health Relevance

The objective of this application is to understand the molecular and cellular mechanisms that govern the migration of neuroblasts in the postnatal forebrain. Proper migration and integration of neuroblasts in the postnatal forebrain is critical t olfactory learning and plasticity, and occurs at ectopic sites of injury in the CNS. Knowledge gained from these studies is expected to lead to a better understanding of the signaling defects that underlie olfactory deficits and associated CNS disorders, and could aid in the development of novel therapeutic strategies to treat brain injury.

Agency
National Institute of Health (NIH)
Institute
National Institute of Mental Health (NIMH)
Type
Research Project (R01)
Project #
2R01MH082808-06
Application #
8586725
Study Section
Intercellular Interactions (ICI)
Program Officer
Panchision, David M
Project Start
2008-07-01
Project End
2018-05-31
Budget Start
2013-08-01
Budget End
2014-05-31
Support Year
6
Fiscal Year
2013
Total Cost
$582,341
Indirect Cost
$274,224
Name
Cold Spring Harbor Laboratory
Department
Type
DUNS #
065968786
City
Cold Spring Harbor
State
NY
Country
United States
Zip Code
11724
Tai, Yilin; Janas, Justyna A; Wang, Chia-Lin et al. (2014) Regulation of chandelier cell cartridge and bouton development via DOCK7-mediated ErbB4 activation. Cell Rep 6:254-63
Murray, D W; Didier, S; Chan, A et al. (2014) Guanine nucleotide exchange factor Dock7 mediates HGF-induced glioblastoma cell invasion via Rac activation. Br J Cancer 110:1307-15
Nakano-Kobayashi, Akiko; Tai, Yilin; Nadif Kasri, Nael et al. (2014) The X-linked mental retardation protein OPHN1 interacts with Homer1b/c to control spine endocytic zone positioning and expression of synaptic potentiation. J Neurosci 34:8665-71
Zhang, Xiaoqun Catherine; Piccini, Antonella; Myers, Michael P et al. (2012) Functional analysis of the protein phosphatase activity of PTEN. Biochem J 444:457-64
Govek, Eve-Ellen; Hatten, Mary E; Van Aelst, Linda (2011) The role of Rho GTPase proteins in CNS neuronal migration. Dev Neurobiol 71:528-53
Nadif Kasri, Nael; Nakano-Kobayashi, Akiko; Van Aelst, Linda (2011) Rapid synthesis of the X-linked mental retardation protein OPHN1 mediates mGluR-dependent LTD through interaction with the endocytic machinery. Neuron 72:300-15
Svitkina, Tatyana; Lin, Wan-Hsin; Webb, Donna J et al. (2010) Regulation of the postsynaptic cytoskeleton: roles in development, plasticity, and disorders. J Neurosci 30:14937-42
Nakano-Kobayashi, Akiko; Kasri, Nael Nadif; Newey, Sarah E et al. (2009) The Rho-linked mental retardation protein OPHN1 controls synaptic vesicle endocytosis via endophilin A1. Curr Biol 19:1133-9