Mice with a null mutation of the TGFα gene have abnormal skin architecture, wavy hair, and curly whiskers and often develop corneal inflammation

Mann, G. Bruce; Fowler, Kerry J.; Gabriel, Anastasia; Nice, Edouard C.; Williams, R.Lindsay; Dunn, Ashley R.

doi:10.1016/0092-8674(93)90227-h

Cited by 552 publications

(333 citation statements)

References 51 publications

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“…Notably, ADAM17-null mice [39,40] display the same aberrant eyelid, hair and whisker phenotypes as TGFα-null mice [41,42], the same altered cardiac valve development as HB-EGF knockout and cleavage-resistant HB-EGF knockin mice [30,43,44], and the diverse epithelial defects and perinatal lethality of EGFR-deficient mice [45][46][47]. Moreover, studies using single-, triple-and quadruple-gene knockout mice lacking ADAMs 9, 12, 15 and/or 17 indicate that only ADAM17 is responsible for the open eyelid and cardiac valve phenotypes of EGFR, TGFα and HB-EGF deficient mice [36].…”

Section: Epithelial Adam17 Is Required For Mammary Developmentmentioning

confidence: 98%

The ADAM17–amphiregulin–EGFR Axis in Mammary Development and Cancer

Sternlicht

Sunnarborg

2008

J Mammary Gland Biol Neoplasia

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In order to fulfill its function of producing and delivering sufficient milk to newborn mammalian offspring, the mammary gland first has to form an extensive ductal network. As in all phases of mammary development, hormonal cues elicit local intra-and inter-cellular signaling cascades that regulate ductal growth and differentiation. Among other things, ductal development requires the epidermal growth factor receptor (EGFR), its ligand amphiregulin (AREG), and the transmembrane metalloproteinase AD-AM17, which can cleave and release AREG from the cell surface so that it may interact with its receptor. Tissue recombination and transplantation studies demonstrate that EGFR phosphorylation and ductal development proceed only when ADAM17 and AREG are expressed on mammary epithelial cells and EGFR is present on stromal cells, and that local administration of soluble AREG can rescue the development of ADAM17-deficient transplants. Thus proper mammary morphogenesis requires the ADAM17-mediated release of AREG from ductal epithelial cells, the subsequent activation of EGFR on stromal cells, and EGFR-dependent stromal responses that in return elicit a new set of epithelial responses, all culminating in the formation of a fully functional ductal tree. This, however, raises new issues concerning what may act upstream, downstream or in parallel with the ADAM17-AREG-EGFR axis, how it may become hijacked or corrupted during the onset and evolution of cancer, and how such ill effects may be confronted.

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Section: Epithelial Adam17 Is Required For Mammary Developmentmentioning

confidence: 98%

The ADAM17–amphiregulin–EGFR Axis in Mammary Development and Cancer

Sternlicht

Sunnarborg

2008

J Mammary Gland Biol Neoplasia

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“…EGF-and amphiregulin-null mice do not have an easily identifiable phenotype [131,132]. Targeted and naturally occurring (waved-1) mutations of TGF-α in mice leads to defects in hair follicle and eye development, phenotypes similar to the spontaneous EGFR mutation of the waved-2 mouse [133][134][135]. Similar to EGFR-null mice, TGF-α-knockout mice also show decreased forebrain neural progenitor cell proliferation, although this does not manifest in an obvious behavioral phenotype in the mice [136].…”

Section: Erbb Members In Mammalian Developmentmentioning

confidence: 99%

The epidermal growth factor receptor family: Biology driving targeted therapeutics

Wieduwilt

Moasser

2008

Cell. Mol. Life Sci.

628

503

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The epidermal growth factor family of receptor tyrosine kinases (ErbBs) plays essential roles in regulating cell proliferation, survival, differentiation and migration. The ErbB receptors carry out both redundant and restricted functions in mammalian development and in the maintenance of tissues in the adult mammal. Loss of regulation of the ErbB receptors underlies many human diseases, most notably cancer. Our understanding of the function and complex regulation of these receptors has fueled the development of targeted therapeutic agents for human malignancies in the last 15 years. Here we review the biology of ErbB receptors, including their structure, signaling, regulation, and roles in development and disease, then briefly touch on their increasing roles as targets for cancer therapy.

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“…EGFR also has several other activating ligands, including transforming growth factor-α (TGFα), heparin-binding EGF-like growth factor (HBEGF), amphiregulin (AR, AREG -Mouse Genome Informatics), betacellulin (BTC), epiregulin (EPR, EREG -Mouse Genome Informatics) and epigen (EPGN). In mice that lack specific ligands, such as TGFα, the absence of an HF phenotype has been interpreted as functional redundancy among ligands (Mann et al, 1993). By contrast, other work suggests that active EGF signalling can inhibit HF development (Cohen and Elliott, 1963).…”

Section: Introductionmentioning

confidence: 99%

KGF and EGF signalling block hair follicle induction and promote interfollicular epidermal fate in developing mouse skin

et al. 2009

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A key initial event in hair follicle morphogenesis is the localised thickening of the skin epithelium to form a placode, partitioning future hair follicle epithelium from interfollicular epidermis. Although many developmental signalling pathways are implicated in follicle morphogenesis, the role of epidermal growth factor (EGF) and keratinocyte growth factor (KGF, also known as FGF7) receptors are not defined. EGF receptor (EGFR) ligands have previously been shown to inhibit developing hair follicles; however, the underlying mechanisms have not been characterised. Here we show that receptors for EGF and KGF undergo marked downregulation in hair follicle placodes from multiple body sites, whereas the expression of endogenous ligands persist throughout hair follicle initiation. Using embryonic skin organ culture, we show that when skin from the sites of primary pelage and whisker follicle development is exposed to increased levels of two ectopic EGFR ligands (HBEGF and amphiregulin) and the FGFR2(IIIb) receptor ligand KGF, follicle formation is inhibited in a time-and dose-dependent manner. We then used downstream molecular markers and microarray profiling to provide evidence that, in response to KGF and EGF signalling, epidermal differentiation is promoted at the expense of hair follicle fate. We propose that hair follicle initiation in placodes requires downregulation of the two pathways in question, both of which are crucial for the ongoing development of the interfollicular epidermis. We have also uncovered a previously unrecognised role for KGF signalling in the formation of hair follicles in the mouse.

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Mice with a null mutation of the TGFα gene have abnormal skin architecture, wavy hair, and curly whiskers and often develop corneal inflammation

Cited by 552 publications

References 51 publications

The ADAM17–amphiregulin–EGFR Axis in Mammary Development and Cancer

The ADAM17–amphiregulin–EGFR Axis in Mammary Development and Cancer

The epidermal growth factor receptor family: Biology driving targeted therapeutics

KGF and EGF signalling block hair follicle induction and promote interfollicular epidermal fate in developing mouse skin

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