Cdk5 is essential for adult hippocampal neurogenesis

Department of Psychiatry, University of Texas Southwestern Medical Center, 5323 Harry Hines Boulevard, Dallas, TX 75390-9070, USA.
Proceedings of the National Academy of Sciences (Impact Factor: 9.81). 12/2008; 105(47):18567-71. DOI: 10.1073/pnas.0810137105
Source: PubMed

ABSTRACT The molecular factors regulating adult neurogenesis must be understood to harness the therapeutic potential of neuronal stem cells. Although cyclin-dependent kinase 5 (Cdk5) plays a critical role in embryonic corticogenesis, its function in adult neurogenesis is unknown. Here, we assessed the role of Cdk5 in the generation of dentate gyrus (DG) granule cell neurons in adult mice. Cre recombinase-mediated conditional knockout (KO) of Cdk5 from stem cells and their progeny in the DG subgranular zone (SGZ) prevented maturation of new neurons. In addition, selective KO of Cdk5 from mature neurons throughout the hippocampus reduced the number of immature neurons. Furthermore, Cdk5 gene deletion specifically from DG granule neurons via viral-mediated gene transfer also resulted in fewer immature neurons. In each case, the total number of proliferating cells was unaffected, indicating that Cdk5 is necessary for progression of adult-generated neurons to maturity. This role for Cdk5 in neurogenesis was activating-cofactor specific, as p35 KO but not p39 KO mice also had fewer immature neurons. Thus, Cdk5 has an essential role in the survival, but not proliferation, of adult-generated hippocampal neurons through both cell-intrinsic and cell-extrinsic mechanisms.

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Available from: James A. Bibb, Jul 30, 2015
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    • "Retrovirus mediated overexpression of dominant negative Cdk5 leads to aberrant dendritic targeting and impaired spine maturation in a significant fraction of targeted adult-born hippocampal neurons , suggesting an intrinsic role for Cdk5 in neuronal maturation (Jessberger et al., 2008; Tobias et al., 2009). On the other hand, conditional deletion of Cdk5 in the NSPC population affected survival of immature neurons, an effect phenocopied in mice lacking the activating cofactor p35 (Lagace et al., 2008). This is particularly interesting because the p35/Cdk5 complex has been shown to be present at the growth cone, where it directly associates with Rac1, hyperphosphorylating its effector Pak1 kinase, resulting in an attenuation of Rac1 signaling (Nikolic et al., 1998). "
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    ABSTRACT: Adult neurogenesis, restricted to specific regions in the mammalian brain, represents one of the most interesting forms of plasticity in the mature nervous system. Adult-born hippocampal neurons play important roles in certain forms of learning and memory, and altered hippocampal neurogenesis has been associated with a number of neuropsychiatric diseases such as major depression and epilepsy. Newborn neurons go through distinct developmental steps, from a dividing neurogenic precursor to a synaptically integrated mature neuron. Previous studies have uncovered several molecular signaling pathways involved in distinct steps of this maturational process. In this context, the small Rho GTPases, Cdc42, Rac1, and RhoA have recently been shown to regulate the morphological and synaptic maturation of adult-born dentate granule cells in vivo. Distinct upstream regulators, including growth factors that modulate maturation and integration of newborn neurons have been shown to also recruit the small Rho GTPases. Here we review recent findings and highlight the possibility that small Rho GTPases may act as central assimilators, downstream of critical input onto adult-born hippocampal neurons contributing to their maturation and integration into the existing dentate gyrus (DG) circuitry.
    Frontiers in Synaptic Neuroscience 08/2013; 5:4. DOI:10.3389/fnsyn.2013.00004
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    • "In males, animals that favored the spatial strategy showed a reduction in cell proliferation compared to cue strategy users, while in females, the opposite was true (Epp and Galea, 2009; Rummel et al., 2010). Furthermore, studies in mice have shown that proteins that regulate neurogenesis, such as Cdk5 (Jessberger et al., 2008; Lagace et al., 2008) and the cAMP responding element binding (CREB) protein (Dworkin and Mantamadiotis, 2010), can differentially facilitate or impair the acquisition of hippocampus-dependent tasks such as the Morris water maze (Ris et al., 2005; Hebda-Bauer et al., 2007) and contextual fear conditioning (Kudo et al., 2003) in males and females. Therefore, the same type of learning paradigm may influence neurogenesis in the hippocampus through different mechanisms in males and females. "
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    ABSTRACT: The structure of the mammalian hippocampus continues to be modified throughout life by continuous addition of neurons in the dentate gyrus. Although the existence of adult neurogenesis is now widely accepted the function that adult generated granule cells play is a topic of intense debate. Many studies have argued that adult generated neurons, due to unique physiological characteristics, play a unique role in hippocampus-dependent learning and memory. However, it is not currently clear whether this is the case or what specific capability adult generated neurons may confer that developmentally generated neurons do not. These questions have been addressed in numerous ways, from examining the effects of increasing or decreasing neurogenesis to computational modeling. One particular area of research has examined the effects of hippocampus dependent learning on proliferation, survival, integration and activation of immature neurons in response to memory retrieval. Within this subfield there remains a range of data showing that hippocampus dependent learning may increase, decrease or alternatively may not alter these components of neurogenesis in the hippocampus. Determining how and when hippocampus-dependent learning alters adult neurogenesis will help to further clarify the role of adult generated neurons. There are many variables (such as age of immature neurons, species, strain, sex, stress, task difficulty, and type of learning) as well as numerous methodological differences (such as marker type, quantification techniques, apparatus size etc.) that could all be crucial for a clear understanding of the interaction between learning and neurogenesis. Here, we review these findings and discuss the different conditions under which hippocampus-dependent learning impacts adult neurogenesis in the dentate gyrus.
    Frontiers in Neuroscience 04/2013; 7:57. DOI:10.3389/fnins.2013.00057 · 3.70 Impact Factor
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    • "Cdk5 is a multifunctional protein kinase in the CNS that has been implicated in cell survival, death, and migration (Lagace et al., 2008; Huang et al., 2009; Kuo et al., 2009). Cdk5 activity has also been reported to promote cancer cell invasion and migration (Strock et al., 2006; Feldmann et al., 2010). "
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    ABSTRACT: Our previous data suggested that the human basic helix-loop-helix transcription factor achaete-scute homologue-1 (hASH1) may stimulate both proliferation and migration in the lung. In the CNS, cyclin-dependent kinase 5 (Cdk5) and its activator p35 are important for neuronal migration that is regulated by basic helix-loop-helix transcription factors. Cdk5/p35 may also play a role in carcinogenesis. In this study, we found that the neuronal activator p35 was commonly expressed in primary human lung cancers. Cdk5 and p35 were also expressed by several human lung cancer cell lines and coupled with migration and invasion. When the kinase activity was inhibited by the Cdk5 inhibitor roscovitine or dominant-negative (dn) Cdk5, the migration of lung cancer cells was reduced. In neuroendocrine cells expressing hASH1, such as a pulmonary carcinoid cell line, knocking down the gene expression by short hairpin RNA reduced the levels of Cdk5/p35, nuclear p35 protein, and migration. Furthermore, expression of hASH1 in lung adenocarcinoma cells normally lacking hASH1 increased p35/Cdk5 activity and enhanced cellular migration. We were also able to show that p35 was a direct target for hASH1. In conclusion, induction of Cdk5 activity is a novel mechanism through which hASH1 may regulate migration in lung carcinogenesis.
    Molecular biology of the cell 06/2012; 23(15):2856-66. DOI:10.1091/mbc.E10-12-1010 · 5.98 Impact Factor
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