Control of Axonal Growth and Regeneration of Sensory Neurons by the p110δ PI 3-Kinase

Medical Research Council Centre for Developmental Neurobiology, King's College London, London, United Kingdom.
PLoS ONE (Impact Factor: 3.23). 02/2007; 2(9):e869. DOI: 10.1371/journal.pone.0000869
Source: PubMed


The expression and function of the 8 distinct catalytic isoforms of PI 3-kinase (PI3K) in the nervous system are unknown. Whereas most PI3Ks have a broad tissue distribution, the tyrosine kinase-linked p110delta isoform has previously been shown to be enriched in leukocytes. Here we report that p110delta is also highly expressed in the nervous system. Inactivation of p110delta in mice did not affect gross neuronal development but led to an increased vulnerability of dorsal root ganglia neurons to exhibit growth cone collapse and decreases in axonal extension. Loss of p110delta activity also dampened axonal regeneration following peripheral nerve injury in adult mice and impaired functional recovery of locomotion. p110delta inactivation resulted in reduced neuronal signaling through the Akt protein kinase, and increased activity of the small GTPase RhoA. Pharmacological inhibition of ROCK, a downstream effector of RhoA, restored axonal extension defects in neurons with inactive p110delta, suggesting a key role of RhoA in p110delta signaling in neurons. Our data identify p110delta as an important signaling component for efficient axonal elongation in the developing and regenerating nervous system.

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Available from: Antonio Bilancio, Sep 30, 2015
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    • "More recently, PI3Kc has been identified in small-to medium-sized neurons, which double stained for IB4 or TRPV1 [13] [25]. Interestingly, PI3Kd has been reported in the ventral horn and peripheral nervous system of E13.5 mice and PI3Kd knock out mice display reduced nerve regeneration after injury [18], this raises the possibility that different isoforms are expressed during development and under conditions of regeneration or extreme physiological stress. Although PI3Ks have been shown to have important roles in Schwann cells and contribute to myelination in Schwann cell– DRG co-cultures [8] [28] [30], our work is the first to imply that the most relevant isoform for Schwann cells is PI3Kb. "
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    ABSTRACT: PI3-kinases (PI3Ks) participate in nociception within spinal cord, dorsal root ganglion (DRG) and peripheral nerves. To extend our knowledge, we immunohistochemically stained for each of the four Class I PI3K isoforms along with several cell specific markers within lumbar spinal cord, DRG and sciatic nerve of naïve rats. Intrathecal and intraplantar isoform specific antagonists were given as pre-treatments before intraplantar carrageenan; pain behavior was then assessed over time. The α-isoform was localized to central terminals of primary afferent fibers in spinal cord laminae IIi-IV as well as to neurons in ventral horn and DRG. The PI3Kβ isoform was the only Class I isoform seen in dorsal horn neurons, it was also observed in DRG, Schwann cells and axonal paranodes. The δ-isoform was found in spinal cord white matter oligodendrocytes and radial astrocytes, while the γ-isoform was seen in a subpopulation of IB4-positive DRG neurons. No isoform co-localized with microglial markers or satellite cells in naïve tissue. Only the PI3Kβ antagonist, but none of the other antagonists, had anti-allodynic effects when administered intrathecally; coincident with reduced pain behavior, this agent completely blocked paw carrageenan-induced dorsal horn 2-amino-3-(3-hydroxy-5-methyl-isoxazol-4-yl) propanoic acid (AMPA) receptor trafficking to plasma membranes. Intraplantar administration of the γ-antagonist prominently reduced pain behavior. These data suggest that each isoform displays specificity with regard to neuronal type as well as to specific tissues. Furthermore, each PI3K isoform has a unique role in development of nociception and tissue inflammation.
    Pain 03/2014; 155(6). DOI:10.1016/j.pain.2014.03.003 · 5.21 Impact Factor
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    • "In addition, a critical role for p110δ in neurons has become increasingly evident over the last years. A study using knockout mice and dominant negative forms of p110δ has shown that p110δ is essential for axonal outgrowth during development and in regenerating neurons (Eickholt et al., 2007). "
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    ABSTRACT: The phosphoinositide 3-kinase (PI3K) complex plays important roles in virtually all cells of the body. The enzymatic activity of PI3K to phosphorylate phosphoinositides in the membrane is mediated by a group of catalytic and regulatory subunits. Among those, the class I catalytic subunits, p110α, p110β, p110γ, and p110δ, have recently drawn attention in the neuroscience field due to their specific dysregulation in diverse brain disorders. While in non-neuronal cells these catalytic subunits may have partially redundant functions, there is increasing evidence that in neurons their roles are more specialized, and confined to distinct receptor-dependent pathways. This review will summarize the emerging role of class I PI3K catalytic subunits in neurotransmitter-regulated neuronal signaling, and their dysfunction in a variety of neurological diseases, including fragile X syndrome, schizophrenia, and epilepsy. We will discuss recent literature describing the use of PI3K subunit-selective inhibitors to rescue brain disease-associated phenotypes in in vitro and animal models. These studies give rise to the exciting prospect that these drugs, originally designed for cancer treatment, may be repurposed as therapeutic drugs for brain disorders in the future.
    Frontiers in Molecular Neuroscience 02/2014; 7:12. DOI:10.3389/fnmol.2014.00012 · 4.08 Impact Factor
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    • "The immune response is controlled by lymphoid and stromal cell function and location in SLO [4]. The PI3K p110δ isoform is expressed preferentially by leukocytes, although it is also detected in other cell types [24], [25], [26], [27], [28]. MZ B cell numbers are extremely low in p110δ-deficient mouse spleen [31], and lack of p110δ or its kinase activity severely impairs germinal center (GC) formation in the spleen after immunization [30], [31], [32], [39]. "
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    ABSTRACT: The role of p110δ PI3K in lymphoid cells has been studied extensively, showing its importance in immune cell differentiation, activation and development. Altered T cell localization in p110δ-deficient mouse spleen suggested a role for p110δ in non-hematopoietic stromal cells, which maintain hematopoietic cell segregation. We tested this hypothesis using p110δ(WT/WT) mouse bone marrow to reconstitute lethally irradiated p110δ(WT/WT) or p110δ(D910A/D910A) (which express catalytically inactive p110δ) recipients, and studied localization, number and percentage of hematopoietic cell subsets in spleen and lymph nodes, in homeostatic conditions and after antigen stimulation. These analyses showed diffuse T cell areas in p110δ(D910A/D910A) and in reconstituted p110δ(D910A/D910A) mice in homeostatic conditions. In these mice, spleen CD4(+) and CD8(+) T cell numbers did not increase in response to antigen, suggesting that a p110δ(D910A/D910A) stroma defect impedes correct T cell response. FACS analysis of spleen stromal cell populations showed a decrease in the percentage of gp38(-)CD31(+) cells in p110δ(D910A/D910A) mice. qRT-PCR studies detected p110δ mRNA expression in p110δ(WT/WT) spleen gp38(-)CD31(+) and gp38(+)CD31(+) subsets, which was reduced in p110δ(D910A/D910A) spleen. Lack of p110δ activity in these cell populations correlated with lower LTβR, CCL19 and CCL21 mRNA levels; these molecules participate in T cell localization to specific spleen areas. Our results could explain the lower T cell numbers and more diffuse T cell areas found in p110δ(D910A/D910A) mouse spleen, as well as the lower T cell expansion after antigen stimulation in p110δ(D910A/D910A) compared with p110δ(WT/WT) mice.
    PLoS ONE 08/2013; 8(8):e72960. DOI:10.1371/journal.pone.0072960 · 3.23 Impact Factor
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