Notch-deficient skin induces a lethal systemic B-lymphoproliferative disorder by secreting TSLP, a sentinel for epidermal integrity.
Epidermal keratinocytes form a highly organized stratified epithelium and sustain a competent barrier function together with dermal and hematopoietic cells. The Notch signaling pathway is a critical regulator of epidermal integrity. Here, we show that keratinocyte-specific deletion of total Notch si...
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| Format: | Article |
| Language: | English |
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Public Library of Science (PLoS)
2008-05-01
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| Series: | PLoS Biology |
| Online Access: | https://journals.plos.org/plosbiology/article/file?id=10.1371/journal.pbio.0060123&type=printable |
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| author | Shadmehr Demehri Zhenyi Liu Jonghyeob Lee Meei-Hua Lin Seth D Crosby Christopher J Roberts Perry W Grigsby Jeffrey H Miner Andrew G Farr Raphael Kopan |
| author_facet | Shadmehr Demehri Zhenyi Liu Jonghyeob Lee Meei-Hua Lin Seth D Crosby Christopher J Roberts Perry W Grigsby Jeffrey H Miner Andrew G Farr Raphael Kopan |
| author_sort | Shadmehr Demehri |
| collection | DOAJ |
| description | Epidermal keratinocytes form a highly organized stratified epithelium and sustain a competent barrier function together with dermal and hematopoietic cells. The Notch signaling pathway is a critical regulator of epidermal integrity. Here, we show that keratinocyte-specific deletion of total Notch signaling triggered a severe systemic B-lymphoproliferative disorder, causing death. RBP-j is the DNA binding partner of Notch, but both RBP-j-dependent and independent Notch signaling were necessary for proper epidermal differentiation and lipid deposition. Loss of both pathways caused a persistent defect in skin differentiation/barrier formation. In response, high levels of thymic stromal lymphopoietin (TSLP) were released into systemic circulation by Notch-deficient keratinocytes that failed to differentiate, starting in utero. Exposure to high TSLP levels during neonatal hematopoiesis resulted in drastic expansion of peripheral pre- and immature B-lymphocytes, causing B-lymphoproliferative disorder associated with major organ infiltration and subsequent death, a previously unappreciated systemic effect of TSLP. These observations demonstrate that local skin perturbations can drive a lethal systemic disease and have important implications for a wide range of humoral and autoimmune diseases with skin manifestations. |
| format | Article |
| id | doaj-art-4bffeee63891429ba7afc1dd280c7d4c |
| institution | OA Journals |
| issn | 1544-9173 1545-7885 |
| language | English |
| publishDate | 2008-05-01 |
| publisher | Public Library of Science (PLoS) |
| record_format | Article |
| series | PLoS Biology |
| spelling | doaj-art-4bffeee63891429ba7afc1dd280c7d4c2025-08-20T02:17:29ZengPublic Library of Science (PLoS)PLoS Biology1544-91731545-78852008-05-0165e12310.1371/journal.pbio.0060123Notch-deficient skin induces a lethal systemic B-lymphoproliferative disorder by secreting TSLP, a sentinel for epidermal integrity.Shadmehr DemehriZhenyi LiuJonghyeob LeeMeei-Hua LinSeth D CrosbyChristopher J RobertsPerry W GrigsbyJeffrey H MinerAndrew G FarrRaphael KopanEpidermal keratinocytes form a highly organized stratified epithelium and sustain a competent barrier function together with dermal and hematopoietic cells. The Notch signaling pathway is a critical regulator of epidermal integrity. Here, we show that keratinocyte-specific deletion of total Notch signaling triggered a severe systemic B-lymphoproliferative disorder, causing death. RBP-j is the DNA binding partner of Notch, but both RBP-j-dependent and independent Notch signaling were necessary for proper epidermal differentiation and lipid deposition. Loss of both pathways caused a persistent defect in skin differentiation/barrier formation. In response, high levels of thymic stromal lymphopoietin (TSLP) were released into systemic circulation by Notch-deficient keratinocytes that failed to differentiate, starting in utero. Exposure to high TSLP levels during neonatal hematopoiesis resulted in drastic expansion of peripheral pre- and immature B-lymphocytes, causing B-lymphoproliferative disorder associated with major organ infiltration and subsequent death, a previously unappreciated systemic effect of TSLP. These observations demonstrate that local skin perturbations can drive a lethal systemic disease and have important implications for a wide range of humoral and autoimmune diseases with skin manifestations.https://journals.plos.org/plosbiology/article/file?id=10.1371/journal.pbio.0060123&type=printable |
| spellingShingle | Shadmehr Demehri Zhenyi Liu Jonghyeob Lee Meei-Hua Lin Seth D Crosby Christopher J Roberts Perry W Grigsby Jeffrey H Miner Andrew G Farr Raphael Kopan Notch-deficient skin induces a lethal systemic B-lymphoproliferative disorder by secreting TSLP, a sentinel for epidermal integrity. PLoS Biology |
| title | Notch-deficient skin induces a lethal systemic B-lymphoproliferative disorder by secreting TSLP, a sentinel for epidermal integrity. |
| title_full | Notch-deficient skin induces a lethal systemic B-lymphoproliferative disorder by secreting TSLP, a sentinel for epidermal integrity. |
| title_fullStr | Notch-deficient skin induces a lethal systemic B-lymphoproliferative disorder by secreting TSLP, a sentinel for epidermal integrity. |
| title_full_unstemmed | Notch-deficient skin induces a lethal systemic B-lymphoproliferative disorder by secreting TSLP, a sentinel for epidermal integrity. |
| title_short | Notch-deficient skin induces a lethal systemic B-lymphoproliferative disorder by secreting TSLP, a sentinel for epidermal integrity. |
| title_sort | notch deficient skin induces a lethal systemic b lymphoproliferative disorder by secreting tslp a sentinel for epidermal integrity |
| url | https://journals.plos.org/plosbiology/article/file?id=10.1371/journal.pbio.0060123&type=printable |
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