Transcriptional Regulatory Role of NELL2 in Preproenkephalin Gene Expression

• Published in: Molecules and cells Vol. 45; no. 8; pp. 537 - 549
• Main Authors: Ha, Chang Man, Kim, Dong Hee, Lee, Tae Hwan, Kim, Han Rae, Choi, Jungil, Kim, Yoonju, Kang, Dasol, Park, Jeong Woo, Ojeda, Sergio R, Jeong, Jin Kwon, Lee, Byung Ju
• Format: Journal Article
• Language: English
• Published: United States Korean Society for Molecular and Cellular Biology 31.08.2022; 한국분자세포생물학회
• Subjects: Animals; Enkephalins; Epidermal Growth Factor - genetics; Epidermal Growth Factor - pharmacology; Gene Expression; Mice; Nerve Tissue Proteins - genetics; Nerve Tissue Proteins - metabolism; NIH 3T3 Cells; Protein Precursors; Rats; 생물학; NELL2; calcium ion; extracellular signal-regulated kinase; preproenkephalin; endoplasmic reticulum; protein kinase C
• ISSN: 1016-8478; 0219-1032
• DOI: 10.14348/MOLCELLS.2022.2051

Preproenkephalin (PPE) is a precursor molecule for multiple endogenous opioid peptides Leu-enkephalin (ENK) and Met-ENK, which are involved in a wide variety of modulatory functions in the nervous system. Despite the functional importance of ENK in the brain, the effect of brain-derived factor(s) on PPE expression is unknown. We report the dual effect of neural epidermal growth factor (EGF)-likelike 2 (NELL2) on PPE gene expression. In cultured NIH3T3 cells, transfection of NELL2 expression vectors induced an inhibition of PPE transcription intracellularly, in parallel with downregulation of protein kinase C signaling pathways and extracellular signal-regulated kinase. Interestingly, these phenomena were reversed when synthetic NELL2 was administered extracellularly. The disruption of NELL2 synthesis resulted in an increase in PPE mRNA level in the rat brain, suggesting that the inhibitory action of intracellular NELL2 predominates the activation effect of extracellular NELL2 on PPE gene expression in the brain. Biochemical and molecular studies with mutant NELL2 structures further demonstrated the critical role of EGF-like repeat domains in NELL2 for regulation of PPE transcription. These are the first results to reveal the spatio-specific role of NELL2 in the homeostatic regulation of PPE gene expression.