SHP-2 Mediates Target-Regulated Axonal Termination and NGF-Dependent Neurite Growth in Sympathetic Neurons

Abstract

The tyrosine phosphatase SHP-2 has been implicated in a variety of signaling pathways, including those mediated by neurotrophins in neurons. To examine the role of SHP-2 in the development of sympathetic neurons, we inhibited the function of SHP-2 in transgenic mice by overexpressing a catalytically inactive SHP-2 mutant under the control of the human dopamine beta-hydroxylase promoter. Expression of mutant SHP-2 did not influence the survival, axon initiation, or pathfinding abilities of the sympathetic neurons. However, mutant SHP-2 expression resulted in an overproduction of sympathetic fibers in sympathetic target organs. This was due to interference with SHP-2 function, as overexpression of wild type SHP-2 had no such effect. In vitro, NGF-dependent neurite growth was inhibited in neurons expressing mutant SHP-2 but not in those expressing wild type SHP-2. Mutant (but not wt) SHP-2 expression also inhibited NGF-stimulated ERK activation. The NGF-dependent survival pathway was less affected than the neurite growth pathway. Our results suggest that NGF-regulated axon growth signals, and to a lesser degree survival signals, are mediated through a SHP-2-dependent pathway in sympathetic neurons. The increased sympathetic innervation in target tissues of neurons expressing mutant SHP-2 may result from interference with normal "stop" signals dependent on signaling by gradients of NGF.

PTP1B and SHP2 in POMC neurons reciprocally regulate energy balance in mice

“…SHP2 also mediates signaling by the c-Ret receptor tyrosine kinase (79,80), which has been shown to be important for normal axon growth and guidance in developing sympathetic neurons (81). Furthermore, NGFstimulated axonal growth is mediated via an SHP2-dependent mechanism in mouse sympathetic neurons (82). Collectively these studies highlight the potential complexity of SHP2 function in mediating neuronal development.…”

A Sympathetic Neuron Autonomous Role for Egr3-Mediated Gene Regulation in Dendrite Morphogenesis and Target Tissue Innervation

“…Some of the genes that were significantly deregulated in the absence of Egr3 have been previously shown to be involved in SNS development including Ngfr (Lee et al, 1994; Bamji et al, 1998; Brennan et al, 1999), Notch1 (Tsarovina et al, 2008), Ret (Enomoto et al, 2001; Tsui-Pierchala et al, 2002), Nf1 (Vogel et al, 1995; Vogel and Parada, 1998), and Ptpn11 (shp-2) (Chen et al, 2002a). More specifically, many of the genes regulated by Egr3 in sympathetic neurons have roles in neurite outgrowth such as Ngfr (Yamashita et al, 1999; Bentley and Lee, 2000; Domeniconi et al, 2005), Ephrin-B1 (Tanaka et al, 2004), Notch1 (Sestan et al, 1999; Huang et al, 2005), Ret (Enomoto et al, 2001; Zhang et al, 2006), Nf1 (Romero et al, 2007), Apbb1 (Ikin et al, 2007), Ptpn11 (shp-2) (Chen et al, 2002a; Perrinjaquet et al, 2010), and Slit2 (Wang et al, 1999; Ozdinler and Erzurumlu, 2002). For example, Ret is a receptor for the glial cell line-derived neurotrophic factor (GDNF) family of ligands, which include GDNF, neurturin, artemin (ARTN), and persephin (Airaksinen et al, 1999; Baloh et al, 2000; Airaksinen and Saarma, 2002).…”

Tyrosine phosphatases such as SHP-2 act in a balance with Src-family kinases in stabilization of postsynaptic clusters of acetylcholine receptors

“…Wild-type SHP-2 (obtained from Dr. J.L. Bixby (University of Miami School of Medicine, Miami, USA)) [58] was subcloned into Bam/Not of pcDNAI-Flag to obtain a SHP-2-Flag ( pcDNAI-SHP-2-Flag ) construct. The constructs were transfected into COS cells using Fugene6 (Roche, Basel, Switzerland) as described below.…”