title: Developmental regulation of TAC1 in peptidergic-induced human mesenchymal stem cells: implication for spinal cord injury in zebrafish.
abstract: Human mesenchymal stem cells (MSCs) are easy to expand, are relatively safe, and can be transplanted in allogeneic recipients as off-the-shelf cells. MSCs can be induced to form functional peptidergic neurons and express the neurotransmitter gene, TAC1. Expression of TAC1 requires that the repressor gene, RE-1 silencing transcription factor (REST), is decreased. This study investigated the molecular pathway in TAC1 induction as MSCs differentiated into neurons and then applied the findings in a model of spinal cord injury (SCI) in zebrafish. We studied the developmental roles of the 2 cAMP response element (CRE) sites: CRE1 and CRE2. Activator protein-1 (AP-1) binding site overlaps with CRE2 (CRE2/AP-1). Reporter gene studies with the 5' regulatory region of TAC1 containing wild-type or mutant CRE sites and, parallel studies with ectopically expressed inhibitor of cAMP proteins (inducible cAMP early repressor) indicated that CRE1 and CRE2/AP-1 are activated at days 6 and 12, respectively. Studies with protein kinase-A (PKA) and Jun N-terminal kinase (JNK) inhibitors in the reporter gene studies, chromatin immunoprecipation assay, and ectopic expression of REST indicated the following pathways: Decrease of REST activated upstream c-Jun N-terminal kinase (JNK). In turn, JNK activated ATF-2 and AP-1 for interaction with CRE1 and CRE2/AP-1, respectively. To apply the finding to SCI, we transplanted 6-day-induced MSCs in transgenic HB9-GFP zebrafish larvae with SCI, in the presence or absence of JNK inhibitors. Imaging and functional studies showed significant improvement in the fish. The repair mechanism involved the activation of JNK. The findings have long-term implications for SCI repair with MSCs.
authors.affiliation: UMDNJ-New Jersey Medical School, Newark, New Jersey 07103, USA.
authors.forename: Nitixa
authors.initials: N
authors.lastname: Patel
authors.forename: Tilman E
authors.initials: TE
authors.lastname: Klassert
authors.forename: Steven J
authors.initials: SJ
authors.lastname: Greco
authors.forename: Shyam A
authors.initials: SA
authors.lastname: Patel
authors.forename: Jessian L
authors.initials: JL
authors.lastname: Munoz
authors.forename: Bobby Y
authors.initials: BY
authors.lastname: Reddy
authors.forename: Margarette
authors.initials: M
authors.lastname: Bryan
authors.forename: Neil
authors.initials: N
authors.lastname: Campbell
authors.forename: Natalia
authors.initials: N
authors.lastname: Kokorina
authors.forename: Hatem E
authors.initials: HE
authors.lastname: Sabaawy
authors.forename: Pranela
authors.initials: P
authors.lastname: Rameshwar
mesh_terms: D051696:Activating Transcription Factors / Q000235:genetics / Q000378:metabolism; D000818:Animals; D001665:Binding Sites; D002478:Cells, Cultured; D056970:Co-Repressor Proteins; D017362:Cyclic AMP Response Element-Binding Protein / Q000235:genetics / Q000378:metabolism; D016222:Fibroblast Growth Factor 2 / Q000494:pharmacology; D005786:Gene Expression Regulation / Q000187:drug effects; D017930:Genes, Reporter; D006801:Humans; D008954:Models, Biological; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism*; D011485:Protein Binding; D016755:Proto-Oncogene Proteins c-jun / Q000235:genetics / Q000378:metabolism; D012097:Repressor Proteins / Q000235:genetics / Q000378:metabolism*; D020218:Response Elements / Q000235:genetics; D015398:Signal Transduction / Q000187:drug effects / Q000235:genetics*; D013119:Spinal Cord Injuries / Q000378:metabolism / Q000473:pathology / Q000628:therapy*; D015320:Tachykinins / Q000235:genetics / Q000378:metabolism*; D018808:Transcription Factor AP-1 / Q000235:genetics / Q000378:metabolism; D014183:Transplantation, Heterologous; D014212:Tretinoin / Q000494:pharmacology; D015027:Zebrafish
chemical_list: D051696:Activating Transcription Factors; D056970:Co-Repressor Proteins; D017362:Cyclic AMP Response Element-Binding Protein; D009419:Nerve Tissue Proteins; D016755:Proto-Oncogene Proteins c-jun; C121019:RCOR1 protein, human; D012097:Repressor Proteins; D015320:Tachykinins; D018808:Transcription Factor AP-1; C045206:neuropeptide K; D016222:Fibroblast Growth Factor 2; D014212:Tretinoin