Expression of Neurotrophins and their Receptors in Human Bone Marrow

Abstract

The expression of neurotrophins and their receptors, the low-affinity nerve growth factor receptor (p75 LNGFR ) and the Trk receptors (TrkA , TrkB, and TrkC) , was investigated in human bone marrow from 16 weeks fetal age to adulthood. Using reverse transcription-polymerase chain reaction , all transcripts encoding for catalytic and truncated human TrkB or TrkC receptors were detected together with trkAI transcripts , whereas trkAII transcripts were found only in control nerve tissues. Transcripts for the homologue of the rat truncated TrkC(ic113) receptor were identified for the first time in human tissue. Stromal adventitial reticular cells were found immunoreactive for all neutrophin receptors. In contrast, hematopoietic cell types were not immunoreactive for p75 LNGFR Nerve growth factor (NGF) 1 is the prototype of a family of related neurotrophic factors known as neurotrophins (NT), which also includes brain-derived neurotrophic factor (BDNF), neurotrophin-3 (NT-3), and neurotrophin-4 (NT-4, also called neurotrophin-5 or NT-5 in humans) (reviewed in Lindsay et al 2 ). NT are trophic factors for the growth, differentiation, and survival of specific subsets of neurons in the developing and mature nervous system. 2 NT can interact with two classes of receptors with distinct ligand affinity and specificity. The low-affinity nerve growth factor receptor, p75 LNGFR , binds all known NT. 3,4 Tyrosine kinase receptors of the Trk family are essential components of NT high-affinity binding sites that trigger neuronal survival, growth, and differentiation. 5 TrkA is the preferred receptor for NGF 6,7 but has a lower efficiency for NT-3 or NT-4/5. TrkB is bound by BDNF and NT-4 and, to a lesser extent, by 9 TrkC is characterized by a unique ligand, NT-3. 10 In some cell lines, TrkA is sufficient to form high-affinity binding sites through homodimerization, 7 whereas p75 LNGFR potentiates TrkA activation by NGF in the PC12 cell line. 11 Variants of tyrosine kinase receptors (TK ϩ ) with insertions in either the extracellular domain (ECD) or the tyrosine kinase domain have been identified for trkA 12,13 and trkC [13][14][15][16] in both human and rat.Truncated receptors lacking the kinase domain (TK Ϫ ) have been described for TrkB and TrkC but not for TrkA. [15][16][17][18] These receptors may function as dominant negative isoforms or immunoadhesins. 13,19,20 Both TK ϩ and TK Ϫ receptors have been detected in neurons while only truncated TrkB and TrkC isoforms have been detected primarily in nonneuronal cells. [15][16][17][18]21 The expression of functional NGF receptors has been detected in several bone marrow-derived cells such as monocytes, 22 mastocytes, 23,24 and B or T cell clones. [25][26][27][28] Among its pleiotropic effects, NGF induces platelet shape changes, 29 triggers monocyte cytotoxic activity, 22 and induces basophilic cell differentiation 30 -32 and mast cell development and degranulation. 24,33 However, NGF receptors have not been consistently detected on bone marrow cells. Although trkA and p75 L...

TrkC signaling is activated in adenoid cystic carcinoma and requires NT-3 to stimulate invasive behavior

“…Remarkably, we found that all these specimens (ACC1-6) expressed the canonical isoform b that encodes a fully active protein (NM_002530), but also contained splicoform d (NM_001243101) that lacks exon 10 producing an 8-amino-acid (aa) in-frame deletion in the juxtamembrane TrkC domain. This isoform, which was expressed in ACC at levels similar to isoform b (data not shown), was previously described as a polymorphism, 41 but its biological significance remains unclear. TrkC signaling varies depending on the availability of its ligand, NT-3.…”

Bone Marrow Mononuclear Cells Promote Proliferation of Endogenous Neural Stem Cells Through Vascular Niches After Cerebral Infarction

“…Although the mechanisms whereby BMMCs promote angiogenesis in vivo remain unclear, our current coculture experiments indicate that BMMCs-induced proliferation of ECs is at least partially attributable to soluble factors. It has been reported that BMCs such as BMMCs [22,46,47] and MSCs [48][49][50] secrete multiple growth factors, including VEGF, glia-derived neurotrophic factor (GDNF), brain-derived neurotrophic factor (BDNF), nerve growth factor (NGF), and hepatocyte growth factor (HGF). In addition, they have been considered to be part of mechanisms responsible for angiogenic, antiapoptotic, and mitogenic effects after cell transplantation [51,52].…”

AML1-ETO fusion protein up-regulates TRKA mRNA expression in human CD34+cells, allowing nerve growth factor-induced expansion

“…However, stromal cells in the bone marrow microenvironment secrete NGF and other cytokines (41); thus, the enhanced expression of the TRKA receptor on AML1-ETO-positive cells could impart a selective growth advantage. The recent finding that AML1-ETO deregulates genes involved in DNA repair underscores the importance of promoting preleukemic stem cell growth to allow for the acquisition of cooperating mutations that could lead to a fully transformed state (27).…”

“…Although NGF͞ TRKA signaling has been most intensively studied in the nervous system, it also participates in hematopoiesis, prostate cancer cell behavior, and angiogenesis (38)(39)(40). NGF is normally expressed by bone marrow stromal cells (41), whereas TRKA is expressed in hematopoietic progenitor cells (42).…”