Reactome | Regulation of NPAS4 gene expression

Regulation of NPAS4 gene expression

Stable Identifier

R-HSA-9768759

Type

Pathway

Species

Homo sapiens

ReviewStatus

5/5

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NPAS4 is predominantly expressed in neuronal cells. In neurons, expression of NPAS4 is regulated by Ca2+, which ties NPAS4 level to neuronal activity (Lin et al. 2008; Zhang et al. 2009; Kim et al. 2010; Mellström et al. 2014; Lobos et al. 2021).

NPAS4 expression is regulated by signaling pathways activated downstream of the N-methyl-D-aspartate (NMDA) receptor and L-type Ca2+ channel (Coba et al. 2008; Lin et al. 2008; Horvath et al. 2021).

In vivo, NPAS4 expression is activated by visual stimulation (Lin et al. 2008), contextual learning (Ramamoorthi et al. 2011), as well as pharmacologically induced generalized seizure (Flood et al. 2004). Chronic stress induces downregulation of NPAS4 gene expression in the hippocampus (Furukawa-Hibi et al. 2015), so does social isolation (Ibi et al. 2008). Adult female mice who were exposed to early maternal separation (early life stress) show upregulation of NPAS4 in the prefrontal cortex later in life (Ryabushkina et al. 2020). NPAS4 is thought to have a neuroprotective effect and is downregulated during neurodegeneration (Ooe et al. 2009; Zhang et al. 2009; Louis Sam Titus et al 2019). NPAS4 level is reduced in the hippocampus of aged, memory-impaired mice (Qiu et al. 2016). Studies in mice indicate that NPAS4 affects synaptic connections in excitatory and inhibitory neurons, neural circuit plasticity, and memory formation (reviewed by Sun and Lin 2016). NPAS4 may be involved in the functioning of the circadian system (Unfried et al. 2010; West et al. 2013; Xu et al. 2021).

Npas4 mRNA levels are downregulated upon infection with Zika virus through an unknown mechanism (Alpuche-Lazcano et al. 2021).

Besides neuronal cells, NPAS4 is also expressed in pancreatic beta cells, where its levels are regulated by intracellular calcium, as in the nervous system (Speckmann et al. 2016).

Literature References

PubMed ID	Title	Journal	Year
34048439	Profound downregulation of neural transcription factor Npas4 and Nr4a family in fetal mice neurons infected with Zika virus Costa, VV, Campolina-Silva, GH, Teixeira, MM, Marim, FM, Saliba, J, Gatignol, A, Ribeiro, LS, Mouland, AJ, Blank, V, Alpuche-Lazcano, SP	PLoS Negl Trop Dis	2021
20070488	Melatonin receptor 1-dependent gene expression in the mouse pars tuberalis as revealed by cDNA microarray analysis and in situ hybridization von Gall, C, Burbach, G, Unfried, C, Korf, HW	J Pineal Res	2010
26987258	Npas4: Linking Neuronal Activity to Memory Sun, X, Lin, Y	Trends Neurosci	2016
23598442	Npas4 is activated by melatonin, and drives the clock gene Cry1 in the ovine pars tuberalis Loudon, AS, Burt, DW, Dupré, SM, Miedzinska, K, Yu, L, Davis, JR, Paton, IR, West, A, McNeilly, AS	Mol Endocrinol	2013
19680447	Nuclear calcium signaling controls expression of a large gene pool: identification of a gene program for acquired neuroprotection induced by synaptic activity Lau, D, Zou, M, Descombes, P, Aso, Y, Lu, L, Ditzel, DA, Bading, H, Delucinge-Vivier, C, Zhang, SJ	PLoS Genet	2009
26222956	Stress increases DNA methylation of the neuronal PAS domain 4 (Npas4) gene Yun, J, Furukawa-Hibi, Y, Nagai, T, Yamada, K	Neuroreport	2015
34348149	A subthreshold synaptic mechanism regulating BDNF expression and resting synaptic strength Horvath, PM, Kavalali, ET, Alten, B, Monteggia, LM, Chanaday, NL	Cell Rep	2021
31883511	The Bdnf and Npas4 genes are targets of HDAC3-mediated transcriptional repression Kim, MS, D'Mello, SR, Louis Sam Titus, ASC, Sharma, D	BMC Neurosci	2019
18815127	Kinase networks integrate profiles of N-methyl-D-aspartate receptor-mediated gene expression in hippocampus Kopanitsa, MV, Grant, SG, Afinowi, NO, Coba, MP, Valor, LM	J Biol Chem	2008
26663079	Npas4 Transcription Factor Expression Is Regulated by Calcium Signaling Pathways and Prevents Tacrolimus-induced Cytotoxicity in Pancreatic Beta Cells Nian, C, Sabatini, PV, Smith, RG, Lynn, FC, Speckmann, T	J Biol Chem	2016
24366545	DREAM controls the on/off switch of specific activity-dependent transcription pathways DeFelipe, J, Maldonado, R, Oliveros, JC, Higuera-Matas, A, Knafo, S, Murtra, P, Gonzalez, P, Dierssen, M, Sahún, I, Bliss, TV, Errington, ML, Zhuo, M, Gomez-Villafuertes, R, Mellström, B, Jefferys, JG, Savignac, M, Naranjo, JR, Kastanauskaite, A, Ruiz-Nuño, A	Mol. Cell. Biol.	2014
20393465	Widespread transcription at neuronal activity-regulated enhancers Greenberg, ME, Bear, DM, Harmin, DA, Kuersten, S, Laptewicz, M, Hemberg, M, Wu, J, Barbara-Haley, K, Kim, TK, Worley, PF, Kreiman, G, Kuhl, D, Bito, H, Costa, AM, Markenscoff-Papadimitriou, E, Gray, JM	Nature	2010
18815592	Activity-dependent regulation of inhibitory synapse development by Npas4 Hauser, JL, Greenberg, ME, Kim, TK, Malik, AN, Hu, LS, Lin, Y, Bloodgood, BL, Koon, AC, Lapan, AD	Nature	2008
34416169	NPAS4 regulates the transcriptional response of the suprachiasmatic nucleus to light and circadian behavior Kim, TK, Greenberg, ME, Joseph, C, Cox, KH, Kulkarni, A, Xu, P, Konopka, G, Jeong, B, Berto, S, Takahashi, JS	Neuron	2021
32190129	Maternal Separation Early in Life Alters the Expression of Genes Npas4 and Nr1d1 in Adult Female Mice: Correlation with Social Behavior Bondar, NP, Ryabushkina, YA, Reshetnikov, VV	Behav Neurol	2020
18182044	Social isolation rearing-induced impairment of the hippocampal neurogenesis is associated with deficits in spatial memory and emotion-related behaviors in juvenile mice Yoneda, Y, Kamei, H, Ibi, D, Kuwahara, Y, Mizoguchi, H, Takuma, K, Tsuritani, K, Koike, H, Nagai, T, Nabeshima, T, Yamada, K	J Neurochem	2008
26563879	Decreased Npas4 and Arc mRNA Levels in the Hippocampus of Aged Memory-Impaired Wild-Type But Not Memory Preserved 11β-HSD1 Deficient Mice Cairns, C, Yau, JL, Kelly, V, Qiu, J, Dunbar, DR, Chapman, KE, Noble, J, Seckl, JR, Carter, R	J Neuroendocrinol	2016
22194569	Npas4 regulates a transcriptional program in CA3 required for contextual memory formation Otto, T, McKinney, RM, Ramamoorthi, K, Fitzmaurice, HL, Lin, Y, Neve, RL, Belfort, GM, Fropf, R	Science	2011
34389673	RyR-mediated Ca²⁺ release elicited by neuronal activity induces nuclear Ca²⁺ signals, CREB phosphorylation, and Npas4/RyR2 expression Ramírez, OA, Córdova, A, Härtel, S, Paula-Lima, A, Vega-Vásquez, I, Hidalgo, C, Adasme, T, Lobos, P, Toledo, J, Cerda, M	Proc Natl Acad Sci U S A	2021
15380003	Nxf and Fbxo33: novel seizure-responsive genes in mice Flood, WD, Moyer, RW, Koblar, SA, Sutherland, GR, Tsykin, A	Eur J Neurosci	2004
19001414	Functional characterization of basic helix-loop-helix-PAS type transcription factor NXF in vivo: putative involvement in an "on demand" neuroprotection system Ooe, N, Kaneko, H, Saito, K, Kobayashi, K, Motonaga, K	J Biol Chem	2009

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Transcriptional Regulation by NPAS4 (Homo sapiens)

Authored

Orlic-Milacic, M (2022-04-08)

Reviewed

Lin, Y (2022-07-29)

Created

Orlic-Milacic, M (2022-03-14)