Predominant expression of Brn-2 in the postmitotic neurons of the developing mouse neocortex

Hagino-Yamagishi, Kimiko; Saijoh, Yukio; Ikeda, Masako; Ichikawa, Masumi; Minamikawa‐Tachino, Reiko; Hamada, Hiroshi

doi:10.1016/s0006-8993(96)01472-2

Cited by 38 publications

(28 citation statements)

References 19 publications

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“…1A) (15) (32). In contrast, in the central nervous system, Brn-2 expression appears to be upregulated in postmitotic neurons of the developing mouse neocortex (19). These observations would indicate that Brn-2 expression is regulated, although the nature of the signal transduction pathways operating to target the Brn-2 promoter is not known.…”

Section: Resultsmentioning

confidence: 89%

The Brn-2 Transcription Factor Links Activated BRAF to Melanoma Proliferation

Goodall

Wellbrock

Dexter

et al. 2004

Molecular and Cellular Biology

108

116

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Malignant melanoma, an aggressive and increasingly common cancer, is characterized by a strikingly high rate (70%) of mutations in BRAF, a key component of the mitogen-activated protein (MAP) kinase signaling pathway. How signaling events downstream from BRAF affect the underlying program of gene expression is poorly understood. We show that the Brn-2 POU domain transcription factor is highly expressed in melanoma cell lines but not in melanocytes or melanoblasts and that overexpression of Brn-2 in melanocytes results in increased proliferation. Expression of Brn-2 is strongly upregulated by Ras and MAP kinase signaling. Importantly, the Brn-2 promoter is stimulated by kinase-activating BRAF mutants and endogenous Brn-2 expression is inhibited by RNA interference-mediated downregulation of BRAF. Moreover, silent interfering RNA-mediated depletion of Brn-2 in melanoma cells expressing activated BRAF leads to decreased proliferation. The results suggest that the high levels of Brn-2 expression observed in melanomas link BRAF signaling to increased proliferation.The mitogen-activated protein (MAP) kinase signaling pathway, comprising the RAS-RAF-MEK-ERK cascade, plays a key role in the cellular response to extracellular signals, and deregulation of the pathway, for example, as a result of activating mutations in Ras, is a feature of many cancers. Three Raf genes have been described (ARAF, BRAF, and CRAF) that are regulated by interaction with Ras, and RAF protein can phosphorylate and activate the MAP kinase kinase MEK. The importance of this signaling pathway in cancer has recently been highlighted by the observation that almost 70% of melanomas and primary nevi exhibit kinase-activating mutations in BRAF (11,26). Understanding how signaling by the MAP kinase pathway affects the underlying program of gene expression is therefore a particularly important issue for melanoma, and it is presumed that deregulation of MAP kinase signaling results in altered expression or activity of key transcription factors, leading to aberrant growth control. The identification of BRAF target genes currently represents a major goal in melanoma biology.The POU domain transcription factor Brn-2 (also called N-Oct3 and POU3F2) (see reference 28 for a review) has been implicated in neuronal differentiation (16) and activation of the corticotropin-releasing hormone gene (22,29). Targeted disruption of the Brn-2 gene in the mouse results in loss of specific neuronal lineages in the hypothalamus and consequent loss of the posterior pituitary gland (25, 29). Brn-2-negative mice therefore die within 10 days after birth, although the specific cause of death is not apparent. Although Brn-2 clearly plays a major role in neuronal development, evidence also implicates it in melanoma growth and survival. Thus, Brn-2 mRNA is overexpressed in melanoma compared to normal melanocytes (15,33,34), and Brn-2 expression is substantially downregulated by differentiating agents (32). Importantly, downregulation of Brn-2 with an antisense strategy resulted in ...

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Section: Resultsmentioning

confidence: 89%

The Brn-2 Transcription Factor Links Activated BRAF to Melanoma Proliferation

Goodall

Wellbrock

Dexter

et al. 2004

Molecular and Cellular Biology

108

116

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“…Rorb belongs to the orphan nuclear receptor family and is preferentially expressed in L4 of the mature neocortex (13,14). Brn1/2 are members of the class III POU (Pit1-Oct1/Oct2-UNC86) domain transcription factors and are preferentially expressed in L2/3 and L5 of the mature neocortex (15)(16)(17). Our detailed analysis of temporal expression profiles of Brn2 and Rorb suggested that UCP neurons initially possess common characteristics and then acquire distinct features.…”

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confidence: 85%

Mutually repressive interaction between Brn1/2 and Rorb contributes to the establishment of neocortical layer 2/3 and layer 4

Oishi

Aramaki

Nakajima

2016

Proc. Natl. Acad. Sci. U.S.A.

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Although several molecules have been shown to play important roles in subtype specification of neocortical neurons, the entire mechanism involved in the specification, in particular, of upper cortical plate (UCP) neurons still remains unclear. The UCP, which is responsible for intracortical connections in the neocortex, comprises histologically, functionally, and molecularly different layer 2/3 (L2/3) and L4. Here, we report the essential interactions between two types of transcription factors, Rorb (RAR-related orphan receptor beta) and Brn1/2 (Brain-1/Brain-2), for UCP specification. We found that Brn2 expression was detected in all upper layers in the immature UCP, but was subsequently restricted to L2/3, accompanied by up-regulation of Rorb in L4, suggesting demarcation of L2/3 and L4 during cortical maturation. Rorb indeed inhibited Brn2 expression and the expression of other L2/3 characteristics, revealed by ectopic expression and knockdown studies. Moreover, this inhibition occurred through direct binding of Rorb to the Brn2 locus. Conversely, Brn1/2 also inhibited Rorb expression and the expression of several L4 characteristics. Together, these results suggest that a mutually repressive mechanism exists between Brn1/2 and Rorb expression and that the established expression of Brn1/2 and Rorb further specifies those neurons into L2/3 and L4, respectively, during UCP maturation.cerebral cortex | cell fate | transcription factor | layer formation T he mammalian neocortex consists of six anatomically distinct layers, each of which contains one or more subtype of neurons, and is characterized by a specific cell morphology, birth date, molecular identity, and connectivity to other regions of the central nervous system. The cortical plate (CP) can be categorized into two populations: lower and upper cortical plate (LCP and UCP). Neurons in the LCP, which consists of layer 5 (L5) and L6, send axons to subcortical targets such as the thalamus, pons, and spinal cord, whereas the UCP, which is known to be much thicker in primates than in rodents, is characterized by corticocortical (intracortical) connections (1-3). The UCP, in rodents, can be further divided into L2/3 and L4. Many L2/3 neurons show a typical pyramidal morphology and send axons to the contralateral cortex, whereas L4 neurons, showing a round shape and granular morphology, receive inputs from the thalamus and transmit the thalamic inputs to local cortical networks (4). Thus, although UCP neurons share at least some features (e.g., intracortical connections), there are apparent differences (e.g., long vs. local projections and cell morphologies). However, how these differences arise during development is poorly understood.Previous studies have revealed the important roles of subtype-or lineage-specific transcription factors (TFs) in the specification of different neuronal subtypes (5-11). One of the intriguing features of how TFs specify neuronal subtypes is that a crucial TF for a given subtype sometimes suppresses other subtypes (3,12). This mechan...

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“…Brn1 expression cannot, therefore, compensate for Brn2 loss in ESCs in contrast to their partially redundant roles in vivo. Secondly, although Brn2 is expressed in ESC-derived radial glial cells in vitro, it is not expressed in radial glial cells of the ventricular zone in the developing cortex, but rather at later stages of differentiation in the sub-ventricular zone (Hagino-Yamagishi et al, 1997).…”

Section: Brn2 Is Upstream Of a Neurogenic Transcriptional Network In mentioning

confidence: 98%

“…Brn2 is expressed in sub-ventricular zone progenitor cells throughout the neuraxis and, upon cell differentiation, is expressed in cortical layers II and III, and in V pyramidal neurons (Hagino-Yamagishi et al, 1997). Brn2-knockout neonates show neuronal loss only in the hypothalamic supraoptic and paraventricular nuclei, where the closely related Brn1 (also known as Pou3f3) is not expressed (Nakai et al, 1995;Schonemann et al, 1995).…”

Section: Introductionmentioning

confidence: 99%

A Brn2–Zic1 axis specifies the neuronal fate of retinoic-acid-treated embryonic stem cells

Urban

Kobi

Ennen

et al. 2015

Journal of Cell Science

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Mouse embryonic stem cells (ESCs) treated with all-trans retinoic acid differentiate into a homogenous population of glutamatergic neurons. Although differentiation is initiated through activation of target genes by the retinoic acid receptors, the downstream transcription factors specifying neuronal fate are less well characterised. Here, we show that the transcription factor Brn2 (also known as Pou3f2) is essential for the neuronal differentiation programme. By integrating results from RNA-seq following Brn2 silencing with results from Brn2 ChIP-seq, we identify a set of Brn2 target genes required for the neurogenic programme. Further integration of Brn2 ChIP-seq data from retinoicacid-treated ESCs and P19 cells with data from ESCs differentiated into neuronal precursors by Fgf2 treatment and that from fibroblasts trans-differentiated into neurons by ectopic Brn2 expression showed that Brn2 occupied a distinct but overlapping set of genomic loci in these differing conditions. However, a set of common binding sites and target genes defined the core of the Brn2-regulated neuronal programme, among which was that encoding the transcription factor Zic1. Small hairpin RNA (shRNA)-mediated silencing of Zic1 prevented ESCs from differentiating into neuronal precursors, thus defining a hierarchical Brn2-Zic1 axis that is essential to specify neural fate in retinoic-acid-treated ESCs.

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Predominant expression of Brn-2 in the postmitotic neurons of the developing mouse neocortex

Cited by 38 publications

References 19 publications

The Brn-2 Transcription Factor Links Activated BRAF to Melanoma Proliferation

The Brn-2 Transcription Factor Links Activated BRAF to Melanoma Proliferation

Mutually repressive interaction between Brn1/2 and Rorb contributes to the establishment of neocortical layer 2/3 and layer 4

A Brn2–Zic1 axis specifies the neuronal fate of retinoic-acid-treated embryonic stem cells

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