Overexpression of nerve growth factor by murine smooth muscle cells: Role of the p75 neurotrophin receptor on sympathetic and sensory sprouting

Abstract

Elevating levels of nerve growth factor (NGF) can have pronounced effects on the survival and maintenance of distinct populations of neurons. We have generated a line of transgenic mice in which NGF is expressed under the control of the smooth muscle α-actin promoter. These transgenic mice have augmented levels of NGF protein in the descending colon and urinary bladder, so these tissues display increased densities of NGF-sensitive sympathetic efferents and sensory afferents. Here we provide a thorough examination of sympathetic and sensory axonal densities in the descending colon and urinary bladder of NGF transgenic mice with and without the expression of the p75 neurotrophin receptor (p75NTR). In response to elevated NGF levels, sympathetic axons (immunostained for tyrosine hydroxylase) undergo robust collateral sprouting in the descending colon and urinary bladder of adult transgenic mice (i.e., those tissues having smooth muscle cells); this sprouting is not augmented in the absence of p75NTR expression. As for sensory axons (immunostained for calcitonin gene-related peptide) in the urinary bladders of transgenic mice, fibers undergo sprouting that is further increased in the absence of p75NTR expression. Sympathetic axons are also seen invading the sensory ganglia of transgenic mice; these fibers form perineuronal plexi around a subpopulation of sensory somata. Our results reveal that elevated levels of NGF in target tissues stimulate sympathetic and sensory axonal sprouting and that an absence of p75NTR by sensory afferents (but not by sympathetic efferents) leads to a further increase of terminal arborization in certain NGF-rich peripheral tissues.

The Delayed-Onset Mechanical Pain Behavior Induced by Infant Peripheral Nerve Injury Is Accompanied by Sympathetic Sprouting in the Dorsal Root Ganglion

“…After adult nerve injury, synthesis of neurotrophins in SGCs surrounding lesioned neurons elevated, which activate the p75NTR or Trk receptors to induce neuropathic pain [38,[47][48][49][50]. As a low-affinity neurotrophin receptor, p75NTR was confirmed to be essential for sympathetic sprouting caused by elevated neurotrophins levels [40]. Knockout of the gene could significantly reduce sympathetic sprouting after nerve injury, which confirmed a causal relationship among neurotrophins, p75NTR, and sympathetic sprouting in adult nerve lesions [51,52].…”

“…Recent studies have revealed that neurotrophin receptors, which are mainly expressed in the satellite glial cells (SGCs) after nerve injury, play an essential role in the development of sympathetic sprouting [38][39][40]. Thus, we evaluated the expression of the low-affinity receptor p75NTR and the high-affinity receptor TrkA in ipsilateral L5 DRG neurons.…”

Myenteric expression of nerve growth factor and the p75 neurotrophin receptor regulate axonal remodeling as a consequence of colonic inflammation in mice

“…Examination of these biological features among NOS1 + myenteric neurons revealed no enhanced survival, somal swelling, or axonal sprouting in response to high levels of NGF protein in the colons of adult SMPpr-NGF transgenic mice, as compared to age-matched wild type siblings. We have previously shown that a loss of functional p75NTR can alter sympathetic and sensory responses to elevated levels of NGF (specifically by enhancing axonal sprouting) (Petrie et al 2013). Though a modest increase in somal size was detected by NOS1 + myenteric neurons in adult NGF/p75 -/-mice (as compared to age-matched NGF/p75 +/+ siblings), neither neuronal numbers nor axonal densities differed among these mice.…”

“…Four lines of mice were used: 1) NGFpr-EGFP mice that display EGFP expression under the control of murine NGF promoter (Kawaja et al, 2011), 2) the progeny of NGF +/-parent mice (B6.129S7-Ngf tm1Gne /J) (Crowley et al, 1994) 3) mice with a knock-out of the p75 neurotrophin receptor (Lee et al, 1992), and 4) the progeny of SMP-NGF/p75 +/-male mice and p75 +/-female mice, where SMP-NGF mice produce NGF under the control of the smooth muscle alpha actin promoter (SMP) (Petrie et al, 2013).…”

Molecular Control of the Neural Crest and Peripheral Nervous System Development

“…p75 NTR can bind all of the neurotrophins, but when compared to the Trks, striking differences in structure and intracellular signal transduction have been discovered (Charalampopoulos et al, 2012). Different deletion mutants of p75 NTR exhibit complex sensory and sympathetic abnormalities that vary depending on the precise mutation (Davies, Lee, & Jaenisch, 1993; Dhanoa, Krol, Jahed, Crutcher, & Kawaja, 2006; Lee et al, 1992; Majdan, Walsh, Aloyz, & Miller, 2001; Petrie et al, 2013; von Schack et al, 2001). Conditional NCC-specific p75 NTR mutants show effects consistent with a disruption in PNS development (Bogenmann et al, 2011).…”