Gene targeting of <i>ErbB3</i> using a Cre‐mediated unidirectional DNA inversion strategy

Qu, Shimian; Rinehart, Cammie; Wu, Hsiao Huei; Wang, Shizhen Emily; Carter, Bruce; Xin, Hong‐Bo; Kotlikoff, Michael I.; Arteaga, Carlos L.

doi:10.1002/dvg.20243

Cited by 34 publications

(36 citation statements)

References 25 publications

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“…1A). ErbB3 was substantially reduced in TEBs of ErbB3 MMTV-KO mice, which use MMTV-Cre transgene expression in the LE to cause genomic recombination at floxed ErbB3 alleles in ErbB3 FL/FL mice (16). Ductal lengthening during puberty was delayed in 8-wk-old ErbB3 MMTV-KO virgin female mice compared with heterozygous ErbB3 FL/+ × MMTVCre controls (Fig.…”

Section: Resultsmentioning

confidence: 90%

“…To understand the role of ErbB3 in mammary gland development, we knocked out ERBB3 in mammary epithelial cells (MECs) and tumors using a mouse mammary tumor virus (MMTV)-driven Cre/lox system (ErbB3 MMTV-KO ) (16), which expresses Cre recombinase primarily in the mammary luminal epithelium (LE). We discovered that ErbB3 is required in the LE, but not in the BE, to support cell proliferation and survival.…”

Section: Mammary Epithelial Differentiation | Erbb3mentioning

confidence: 99%

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The receptor tyrosine kinase ErbB3 maintains the balance between luminal and basal breast epithelium

Balko¹,

Miller

Morrison³

et al. 2011

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

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ErbB3 harbors weak kinase activity, but strongly activates downstream phosphatidylinositol 3-kinase/Akt signaling through heterodimerization with and activation by other ErbB receptor tyrosine kinases. We report here that ErbB3 loss in the luminal mammary epithelium of mice impaired Akt and MAPK signaling and reduced luminal cell proliferation and survival. ERBB3 mRNA expression levels were highest in luminal mammary populations and lowest in basal cell/stem cell populations. ErbB3 loss in mammary epithelial cells shifted gene expression patterns toward a mammary basal cell/stem cell signature. ErbB3 depletion-induced gene expression changes were rescued upon activation of Akt and MAPK signaling. Interestingly, proliferation and expansion of the mammary basal epithelium (BE) occurred upon ErbB3 targeting in the luminal epithelium, but not upon its targeting in the BE. Multiple cytokines, including interleukin 6, were induced upon ErbB3 depletion in luminal epithelium cells, which increased growth of BE cells. Taken together, these results suggest that ErbB3 regulates the balance of differentiated breast epithelial cell types by regulating their growth and survival through autocrine-and paracrinesignaling mechanisms.A berrant regulation of the ErbB family of receptor tyrosine kinases (RTKs) and their ligands is common in human cancers (1-4). This family consists of four members: HER1/ErbB1/ EGFR (epidermal growth factor receptor), HER2/ErbB2/Neu, HER3/ErbB3, and HER4/ErbB4. Except for ErbB3, which has weak kinase activity, the ErbB RTKs exhibit dimerization-induced phosphorylation and catalytic activation. In response to ligand binding, ErbBs form homodimers and heterodimers with other ErbB coreceptors. ErbB3 relies on transphosphorylation by heterodimeric partners to induce signal transduction (5-7).ErbB RTKs are required for breast development, although each receptor bears a unique spatiotemporal expression pattern. ErbB2 loss in the mammary epithelium delays ductal elongation during puberty and disorganizes cells within terminal end buds (TEBs) (8-10). EGFR and ErbB4 are not required for mammary ductal development. Rather, EGFR is expressed in the basal epithelium (BE) and in the mammary stroma, and ErbB4 is necessary for milk production (11,12). Although classical knockout of mouse ErbB3 results in embryonic lethality (13), transplant experiments showed that ErbB3 drives growth of the mammary epithelium during puberty (8). Although the mechanism(s) by which ErbB2 and ErbB3 regulate growth of the ductal epithelium are currently unknown, such knowledge will impact our understanding of the earliest events contributing to the formation of ErbB2/HER2-amplified breast cancers, which account for 20-30% of all breast cancers. ErbB3-ErbB2 heterodimers are the most potent oncogenic ErbB-signaling pair due in part to strong ErbB3-induced phosphatidylinositol 3-kinase (PI3K) activation in response to ErbB3 tyrosine phosphorylation at six PI3K interaction motifs (14,15).To understand the role of ErbB3 in mammary gland dev...

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Section: Resultsmentioning

confidence: 90%

Section: Mammary Epithelial Differentiation | Erbb3mentioning

confidence: 99%

The receptor tyrosine kinase ErbB3 maintains the balance between luminal and basal breast epithelium

Balko¹,

Miller

Morrison³

et al. 2011

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

Self Cite

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“…ErbB3 Deletion in Schwann Cells-Schwann cells were isolated from postnatal day 4 -5 mice homozygous for a floxed ErbB3 allele previously described (21). The cells were infected with an adenovirus expressing green fluorescent protein or Cre recombinase (22).…”

Section: Methodsmentioning

confidence: 99%

“…Schwann cells were isolated from transgenic mice harboring a conditional allele for ErbB3 (21) and the cells infected with an adenovirus expressing Cre recombinase or green fluorescent protein, as a control. After 48 h, ErbB3 protein expression and axonal membrane-mediated activation of ERK and Akt were attenuated (Fig.…”

Section: Nf-b Stimulation By Axonal Membranes Requires Erbb2 and Erbb3mentioning

confidence: 99%

Axonal Neuregulin 1 Type III Activates NF-κB in Schwann Cells during Myelin Formation

Limpert

Carter

2010

Journal of Biological Chemistry

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The formation of myelin requires a series of complex signaling events initiated by the axon to surrounding glial cells, which ultimately respond by tightly wrapping the axon with layers of specialized plasma membrane thereby allowing for saltatory conduction. Activation of the transcription factor NF-B in Schwann cells has been suggested to be critical for these cells to differentiate into a myelinating phenotype; however, the mechanisms by which it is activated have yet to be elucidated. Here, we demonstrate that axonal membranes are sufficient to pro-

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“…To circumvent this, we used Cre-Lox-based conditional knockout approach to knock out the Erbb3 gene specifically in the CNS. Floxed Erbb3 mice (Qu et al, 2006) were crossed with GFAP::Cre mice (Zhuo et al, 2001). Cre expression in GFAP::Cre mice occurs as early as E13.5 in precursor cells in the cerebellum that give rise to both GNs and glia.…”

Section: Loss Of Erbb3 In the Brain Causes Motor Impairmentsmentioning

confidence: 99%

ERBB3-mediated regulation of Bergmann glia proliferation in cerebellar lamination

et al. 2015

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Cortical lamination is crucial for the assembly of cerebellar circuitry. In this process, granule neurons (GNs) migrate along Bergmann glia (BG), which are specialized astroglial cells, from the external granule layer to the internal granule layer. However, the molecular mechanisms underlying BG development are not well understood. Here, we show that GFAP::Cre;Erbb3 F/F mice, which lack Erbb3 in both radial glia and neurons, exhibit impairments in balance and motor coordination. Cerebellar lamination is aberrant, with misplaced Purkinje neurons and GN clusters. These phenotypes were not observed in Math1::CreER T2 ;Erbb3 F/F mice, where the Erbb3 gene was deleted in GNs, suggesting involvement of non-neuronal Erbb3 in cerebellar lamination. Mechanistic studies indicate that ERBB3 is crucial for the proliferation of BG, which are required for GN migration. These observations identify a crucial role for ERBB3 in cerebellar lamination and reveal a novel mechanism that regulates BG development.

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Gene targeting of ErbB3 using a Cre‐mediated unidirectional DNA inversion strategy

Cited by 34 publications

References 25 publications

The receptor tyrosine kinase ErbB3 maintains the balance between luminal and basal breast epithelium

The receptor tyrosine kinase ErbB3 maintains the balance between luminal and basal breast epithelium

Axonal Neuregulin 1 Type III Activates NF-κB in Schwann Cells during Myelin Formation

ERBB3-mediated regulation of Bergmann glia proliferation in cerebellar lamination

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