Abstract
Recent studies have led to the exciting idea that adult-born neurons in the olfactory bulb (OB) may be critical for complex forms of olfactory behavior in mice. However, signaling mechanisms regulating adult OB neurogenesis are not well defined. We recently reported that extracellular signal-regulated kinase (ERK) 5, a MAP kinase, is specifically expressed in neurogenic regions within the adult brain. This pattern of expression suggests a role for ERK5 in the regulation of adult OB neurogenesis. Indeed, we previously reported that conditional deletion of erk5 in adult neurogenic regions impairs several forms of olfactory behavior in mice. Thus, it is important to understand how ERK5 regulates adult neurogenesis in the OB. Here we present evidence that shRNA suppression of ERK5 in adult neural stem/progenitor cells isolated from the subventricular zone (SVZ) reduces neurogenesis in culture. By contrast, ectopic activation of endogenous ERK5 signaling via expression of constitutive active MEK5, an upstream activating kinase for ERK5, stimulates neurogenesis. Furthermore, inducible and conditional deletion of erk5 specifically in the neurogenic regions of the adult mouse brain interferes with cell cycle exit of neuroblasts, impairs chain migration along the rostral migratory stream and radial migration into the OB. It also inhibits neuronal differentiation and survival. These data suggest that ERK5 regulates multiple aspects of adult OB neurogenesis and provide new insights concerning signaling mechanisms governing adult neurogenesis in the SVZ-OB axis.
Highlights
The ability of humans and other vertebrates to detect and distinguish between thousands of different odorants is critical for nutrition and survival
ERK5 Protein Expression in the subventricular zone (SVZ) and rostral migratory stream (RMS) We reported that ERK5 is expressed in the subgranular zone (SGZ) of the dentate gyrus and in the SVZRMS of the adult mouse brain [15,25,26,27]
When we examined the relative distribution of adult-born cells at 7 d post-BrdU injection along the SVZ-RMS-olfactory bulb (OB) axis, more BrdU+ cells remained in the SVZ and the vertical limb of the RMS, while fewer reached the OB in ERK5 inducible and conditional knockout (icKO) mice (Fig. 7B), even though the total number of BrdU+ cells was similar between control and ERK5 icKO mice (Fig. 7C)
Summary
The ability of humans and other vertebrates to detect and distinguish between thousands of different odorants is critical for nutrition and survival. Normal ongoing adult neurogenesis occurs in two principle regions of the adult mammalian brain including the subventricular zone (SVZ) along the lateral ventricles (LV) [1,2,3,4]. Recent studies have led to the interesting finding that adult neurogenesis in the OB may influence several complex forms of olfactory behavior in mice [5,9,10,11,12,13,14,15]. Adult neurogenesis in the OB is a model system to study stem cell biology, regenerative and reparative medicine, and plasticity of the adult nervous system. It is critical to elucidate signaling mechanisms regulating adult SVZ-OB neurogenesis
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