Control of Drosophila perineurial glial growth by interacting neurotransmitter-mediated signaling pathways

112

148

We hypothesized that cystine/glutamate transporters (xCTs) might be critical regulators of ambient extracellular glutamate levels in the nervous system and that misregulation of this glutamate pool might have important neurophysiological and/or behavioral consequences. To test this idea, we identified and functionally characterized a novel Drosophila xCT gene, which we subsequently named "genderblind" ( gb). Genderblind is expressed in a previously overlooked subset of peripheral and central glia.

Section: Genderblind Is Expressed Throughout Developmentmentioning

confidence: 99%

Nonvesicular Release of Glutamate by Glial xCT Transporters Suppresses Glutamate Receptor ClusteringIn Vivo

Augustin¹,

Grosjean²,

Chen³

et al. 2007

112

148

“…This is not an effect of the classical Ras-MAPK (mitogen-activated protein kinase) pathway, but rather results from abnormalities in the cAMP-mediated opening of the channel. Enlarged peripheral nerves in NF1 mutant flies result from Ras or non-Ras pathway defects (Yager et al, 2001). Neurofibromin is also a substrate of PKA.…”

Section: Schwann Cell Tumorsmentioning

confidence: 99%

Mechanisms and Roles of Axon-Schwann Cell Interactions

Corfas¹,

Velardez²,

Ko³

et al. 2004

176

130

Schwann cells (SCs) cover most of the surface of all axons in peripheral nerves. Axons and these glial cells are not only in intimate physical contact but also in constant and dynamic communication, each one influencing and regulating the development, function, and maintenance of the other. In recent years, there has been significant progress in the understanding of the molecular mechanisms of axon-Schwann cell interactions, particularly those relevant for postnatal development and maintenance of nerve function and structure. In this review, we discuss recent progress in four aspects of axon-Schwann cell interactions, including the roles of the neuregulin1 (NRG1)-erbB signaling pathway, the mechanisms underlying the formation and function of the node of Ranvier, the role of perisynaptic Schwann cells at the neuromuscular junction, and the mechanisms that generate Schwann cell tumors.Along the entire length of mammalian peripheral nerves, axons of motor, sensory, and autonomic neurons are in close association with SCs. The intimate contact between SCs and peripheral axons provided a first indication that these cells interact in important ways. In the mature nervous system, Schwann cells can be divided into four classes: myelinating cells (MSCs), nonmyelinating cells (NMSCs), perisynaptic Schwann cells (PSCs) (also known as terminal Schwann cells), and satellite cells of peripheral ganglia. These classes are based on their morphology, biochemical makeup, and the neuronal types (or area of their axons) with which they associate. MSCs, the best characterized SC, wrap around all large-diameter axons, including all motor neurons and some sensory neurons. Each MSC associates with a single axon and creates the myelin sheath necessary for saltatory nerve conduction (Fig. 1 A). NMSCs associate with small-diameter axons of C-fibers emanating from many sensory and all postganglionic sympathetic neurons. Each NMSC wraps around several sensory axons to form a Remak bundle, keeping individual axons separated by thin extensions of the Schwann cell body (Fig. 1 B).

“…Regulation of peripheral nerve growth by a neuron-glia signaling pathway Yager et al (2001) reported that perineurial glial growth in Drosophila peripheral nerves is regulated by several genes. These genes include Nf1, which is the Drosophila ortholog of human Nf1, push, which is thought to encode an E3 ubiquitin ligase and two genes implicated in neurotransmitter signaling: amnesiac, which is thought to encode a neuropeptide similar to vertebrate pituitary adenylate cyclase-activating polypeptide (Feany and Quinn, 1995), and inebriated (ine), which encodes a member of the Na ϩ /Cl Ϫ -dependent neurotransmitter transporter family (Soehnge et al, 1996).…”

Section: Discussionmentioning

confidence: 99%

“…Larvae were collected only during the first and second days after the initial third-instar larvae appeared. The dissections, fixations, and stainings were performed as described previously (Yager et al, 2001). Perineurial glial thickness was measured from the edge of the nerve to the axon-containing lumen and averaged from eight measurements made 12:00, 3:00, 6:00, and 9:00 and four positions in between.…”

Section: Methodsmentioning

confidence: 99%

Phosphatidylinositol 3-Kinase and Akt Nonautonomously Promote Perineurial Glial Growth inDrosophilaPeripheral Nerves

Lavery¹,

Hall²,

Yager³

et al. 2007

Drosophila peripheral nerves, structured similarly to their mammalian counterparts, comprise a layer of motor and sensory axons wrapped by an inner peripheral glia (analogous to the mammalian Schwann cell) and an outer perineurial glia (analogous to the mammalian perineurium). Growth and proliferation within mammalian peripheral nerves are increased by Ras pathway activation: loss-of-function mutations in Nf1, which encodes the Ras inhibitor neurofibromin, cause the human genetic disorder neurofibromatosis, which is characterized by formation of neurofibromas (tumors of peripheral nerves). However, the signaling pathways that control nerve growth downstream of Ras remain incompletely characterized. Here we show that expression specifically within the Drosophila peripheral glia of the constitutively active Ras V12 increases perineurial glial thickness. Using chromosomal loss-of-function mutations and transgenes encoding dominant-negative and constitutively active proteins, we show that this nonautonomous effect of Ras V12 is mediated by the Ras effector phosphatidylinositol 3-kinase (PI3K) and its downstream kinase Akt. We also show that the nonautonomous, growthpromoting effects of activated PI3K are suppressed by coexpression within the peripheral glia of FOXO ϩ (forkhead box O) a transcription factor inhibited by Akt-dependent phosphorylation. We suggest that Ras-PI3K-Akt activity in the peripheral glia promotes growth of the perineurial glia by inhibiting FOXO. In mammalian peripheral nerves, the Schwann cell releases several growth factors that affect the proliferative properties of neighbors. Some of these factors are oversecreted in Nf1 mutants. Our results raise the possibility that neurofibroma formation in individuals with neurofibromatosis might result in part from a Ras-PI3K-Akt-dependent inhibition of FOXO within Schwann cells.