NTF3 Is a Novel Target Gene of the Transcription Factor POU3F2 and Is Required for Neuronal Differentiation

Abstract

POU-homeodomain transcription factor POU3F2 is a critical transcription factor that participates in neuronal differentiation. However, little is known about its downstream mediators. Here genome-wide analyses of a human neuronal differentiation cell model, NT2D1, suggested neurotrophin-3 (NTF3), a key mediator of neuronal development during the early neurogenic period, as a putative regulatory target of POU3F2. Western blot, cDNA microarray, and real-time quantitative PCR analyses showed that POU3F2 and NTF3 were upregulated during neuronal differentiation. Next-generation-sequence-based POU3F2 chromatin immunoprecipitation-sequencing and genome-wide in silico prediction demonstrated that POU3F2 binds to the NTF3 promoter during neuronal differentiation. Furthermore, unidirectional deletion or mutation of the binding site of POU3F2 in the NTF3 promoter decreased promoter-driven luciferase activity, indicating that POU3F2 is a positive regulator of NTF3 promoter activity. While NTF3 knockdown resulted in decreased viability and differentiation of NT2D1 cells, and POU3F2 knockdown downregulated NTF3 expression, recombinant NTF3 significantly rescued viable neuronal cells from NTF3- or POU3F2-knockdown cell cultures. Moreover, immunostaining showed colocalization of POU3F2 and NTF3 in developing mouse neurons. Thus, our data suggest that NTF3 is a novel target gene of POU3F2 and that the POU3F2/NTF3 pathway plays a role in the process of neuronal differentiation.Electronic supplementary materialThe online version of this article (10.1007/s12035-018-0995-y) contains supplementary material, which is available to authorized users.

Identification of prognostic factors for intrahepatic cholangiocarcinoma using long non-coding RNAs-associated ceRNA network

“…FOXO1 expression was reduced in patients with type II diabetes mellitus, and that the downregulation of FOXO1 induces insulin resistance states that qualitatively and quantitatively mimic the function of adipocytes from patients with type II diabetes mellitus [40]. NTF3, belonging to the neurotrophic factor family which encompasses nerve growth factor, brain-derived neurotrophic factor, and neurotrophic factor 4/5, has become a key mediator of neuronal development in early neurogenesis and throughout adulthood [41]. Moreover, the correlation between NTF3 and diabetes mellitus has been identified [42].…”

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“…Mice with only one functional copy of the NTF3 gene showed a smaller cross-sectional fiber area and more densely distributed muscle fibers [13]. Upregulation of NTF3, stimulated by the transcription factor POU3F2, is present during neuronal differentiation [14]. The neocortex has multiple layers originated by cell fate restriction of cortical progenitors and NTF3 induces cell fate switches by controlling a feedback signal between postmitotic neurons and progenitors.…”

Identification of prognostic factors for intrahepatic cholangiocarcinoma using long non-coding RNAs-associated ceRNA network

“…FOXO1 expression was reduced in patients with type II diabetes mellitus, and that the downregulation of FOXO1 induces insulin resistance states that qualitatively and quantitatively mimic the function of adipocytes from patients with type II diabetes mellitus [40]. NTF3, belonging to the neurotrophic factor family which encompasses nerve growth factor, brain-derived neurotrophic factor, and neurotrophic factor 4/5, has become a key mediator of neuronal development in early neurogenesis and throughout adulthood [41]. Moreover, the correlation between NTF3 and diabetes mellitus has been identi ed [42].…”