NPAS4 regulates expression of target genes

Stable Identifier
R-HSA-9768919
Type
Pathway
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Homo sapiens
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5/5
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NPAS4 is a basic helix loop helix (bHLH) transcription factor that needs to dimerize with another bHLH protein, either ARNT, ARNT2 or ARNTL, in order to be able to bind to target DNA (Ooe et al. 2004; Ooe et al. 2009; Brigidi et al. 2019).

NPAS4 is implicated as a transcriptional regulator of genes involved in neuronal development such as CDK5 (Yun et al. 2013), CDK5R1 (Yun et al. 2013), RBFOX3 (NeuN) (Yun et al. 2013), BDNF (Pruunsild et al. 2011) and RET (Sribudiani et al. 2011), genes involved in synaptogenesis and synaptic transmission such as NPTX2 (Lin et al. 2008), MDM2 (Yoshihara et al. 2014; Lv et al. 2021), FOS (Ramamoorthi et al. 2011), IQSEC3 (Kim et al. 2021), PLK2 (Weng et al. 2018) and possibly other genes (Lin et al. 2008; Shan et al. 2018), circadian rhythm-related genes such as NAMPT (West et al. 2013), and genes involved in neuroprotection upon injury such as GEM (Takahashi et al. 2021), SYT10 (Woitecki et al. 2016) and possibly other genes (Qiu et al. 2013). In pancreatic beta-cell, NPAS4 is implicated as a regulator of insulin synthesis under stress conditions (Sabatini et al. 2013).

The circadian clock regulated gene CRY1 was identified as NPAS4 target gene in sheep brain (West et al. 2013), but this finding was not reproduced in the high throughput identification of NPAS4 targets in rat primary neurons (Brigidi et al. 2019). The DBNL gene, encoding Drebrin, a dendrytic cytoskeleton modulator, was initially identified as a gene directly upregulated by Npas4 (Ooe et al. 2004), but a high throughput study of NPAS4 targets showed DBNL gene expression to be repressed by NPAS4, although not significantly (Brigidi et al. 2019).

NPAS4 is expressed in endothelial cells and may play a role in angiogenesis (Esser et al. 2017).
Literature References
PubMed ID Title Journal Year
20977903 Variants in RET associated with Hirschsprung's disease affect binding of transcription factors and gene expression

Sribudiani, Y, Hofstra, RM, Metzger, M, Osinga, J, Burns, AJ, Rey, A, Thapar, N

Gastroenterology 2011
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
23172225 Neuronal Per Arnt Sim (PAS) domain protein 4 (NPAS4) regulates neurite outgrowth and phosphorylation of synapsin I

Yun, J, Greenberg, ME, Kaibuchi, K, Kuroda, K, Furukawa-Hibi, Y, Nagai, T, Yamada, K

J. Biol. Chem. 2013
34349016 Ras-like Gem GTPase induced by Npas4 promotes activity-dependent neuronal tolerance for ischemic stroke

Takahashi, H, Tsuboi, A, Kato, S, Hioki, H, Matsui, TK, Yamamoto, T, Fujioka, M, Mori, E, Kobayashi, K, Asahina, R

Proc Natl Acad Sci U S A 2021
14701734 Identification of a novel basic helix-loop-helix-PAS factor, NXF, reveals a Sim2 competitive, positive regulatory role in dendritic-cytoskeleton modulator drebrin gene expression

Nakatuka, I, Ooe, N, Mikami, N, Kaneko, H, Saito, K

Mol. Cell. Biol. 2004
29429933 Npas4 Is a Critical Regulator of Learning-Induced Plasticity at Mossy Fiber-CA3 Synapses during Contextual Memory Formation

Dushko, M, Xu, W, Zemoura, K, Alviña, K, Chung, K, Lin, Y, Castillo, PE, Sørensen, AT, Lutzu, S, Yelhekar, TD, Zhang, Y, Rich, D, Garcia-Dominguez, D, Garcia, RI, Hung, M, Ku, T, Weng, FJ

Neuron 2018
31585079 Genomic Decoding of Neuronal Depolarization by Stimulus-Specific NPAS4 Heterodimers

Lin, PA, Brigidi, GS, Hayes, MGB, Bartlett, A, Bloodgood, BL, Heinz, S, Texari, L, Ecker, JR, Delos Santos, NP, Benner, C, Hartzell, AL

Cell 2019
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
28082451 The neuronal transcription factor NPAS4 is a strong inducer of sprouting angiogenesis and tip cell formation

Allen, A, Schmidt, M, Charlet, A, Epting, D, Moser, M, Bode, C, Esser, JS, Patterson, C, Lother, A, Heck, S

Cardiovasc Res 2017
29222951 Neuronal PAS domain protein 4 (Npas4) controls neuronal homeostasis in pentylenetetrazole-induced epilepsy through the induction of Homer1a

Shan, W, Furukawa-Hibi, Y, Sokabe, M, Itoh, N, Nagai, T, Nabeshima, T, Yamada, K, Tanaka, M

J Neurochem 2018
23774321 Mitochondrial calcium uniporter Mcu controls excitotoxicity and is transcriptionally repressed by neuroprotective nuclear calcium signals

Skehel, PA, Hardingham, GE, Hagenston, AM, Wyllie, DJ, Qiu, J, Tan, YW, Bading, H, Kneisel, N, Martel, MA

Nat Commun 2013
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
33411316 Neuroprotective Effects Against Cerebral Ischemic Injury Exerted by Dexmedetomidine via the HDAC5/NPAS4/MDM2/PSD-95 Axis

Chen, W, Cheng, Q, Lv, H, Chen, J, Li, Y

Mol Neurobiol 2021
23656887 Npas4 is a novel activity-regulated cytoprotective factor in pancreatic β-cells

Zarrouki, B, Nian, C, Westwell-Roper, CY, Uy, RA, Sabatini, PV, Krentz, NA, Lynn, FC, Shapiro, AM, Poitout, V

Diabetes 2013
25088421 Npas4 regulates Mdm2 and thus Dcx in experience-dependent dendritic spine development of newborn olfactory bulb interneurons

Takahashi, H, Tsuboi, A, Yoshihara, S, Kinoshita, M, Kitsuki, M, Hirai, H, Furukawa-Hibi, Y, Nagai, T, Tatsumi, K, Nishimura, N, Yamada, K, Asahina, R

Cell Rep 2014
21368041 Identification of cis-elements and transcription factors regulating neuronal activity-dependent transcription of human BDNF gene

Orav, E, Timmusk, T, Koppel, I, Pruunsild, P, Sepp, M

J. Neurosci. 2011
34289353 Npas4 regulates IQSEC3 expression in hippocampal somatostatin interneurons to mediate anxiety-like behavior

Um, JW, Kim, J, Tabuchi, K, Park, D, Ko, J, Kim, D, Cheong, E, Lee, D, Jeon, J, Jung, H, Mori, T, Kim, S, Kim, J, Hong, S, Kim, H

Cell Rep 2021
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