The ErbB3 receptor tyrosine kinase negatively regulates Paneth cells by PI3K-dependent suppression of Atoh1
The ErbB3 receptor tyrosine kinase negatively regulates Paneth cells by PI3K-dependent suppression of Atoh1
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DOI：
10.1038/cdd.2017.27
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发表时间：
2017-05-01
影响因子：
12.4
通讯作者：
Frey, Mark R.
中科院分区：
文献类型：
--
作者：
Almohazey, Dana;Lo, Yuan-Hung;Frey, Mark R.
Paneth细胞(PC)是位于肠道隐窝底部的一种分泌性细胞群，通过释放包括溶菌酶和防御素在内的抗菌肽，以生长因子支持肠道干细胞(ISC)，参与先天免疫。PC功能障碍与克罗恩病和坏死性小肠结肠炎等疾病有关，但调节PC发育和功能的具体途径尚不完全清楚。在这里，我们测试了神经调节蛋白受体ErbB3在PC分化和ISC生态位控制中的作用。肠道上皮细胞ErbB3基因敲除可使成体小鼠回肠中的成熟PC数量显著增加，且早在出生后7d就可导致PC的早熟出现。ErbB3缺失对其他分泌谱系无影响，但增加ISC标志物Lgr5的表达。ErbB3缺失的肠道中，决定分泌命运所需的Atoh1转录因子水平升高，而Atoh1(+)细胞中ErbB3水平降低，这表明相互的负调控。ErbB3缺失的肠祖细胞表现出PI3K-Akt和ERK MAPK通路的激活减少。在HT29细胞中抑制这些通路会增加Atoh1和PC标记物Lyz的水平。相反，ErbB3的激活以PI3K依赖的方式抑制Lyz和Atoh1。ErbB3缺失的肠道中PC间隔区的扩张伴随着内质网应激和炎症标志物的升高，这增加了ErbB3对PC的负调控是维持体内平衡所必需的可能性。综上所述，我们的数据表明ErbB3通过PI3K介导的Atoh1水平抑制PC分化来限制PC数量，这对ISC生态位的调控具有重要意义。
Paneth cells (PCs), a secretory population located at the base of the intestinal crypt, support the intestinal stem cells (ISC) with growth factors and participate in innate immunity by releasing antimicrobial peptides, including lysozyme and defensins. PC dysfunction is associated with disorders such as Crohn's disease and necrotizing enterocolitis, but the specific pathways regulating PC development and function are not fully understood. Here we tested the role of the neuregulin receptor ErbB3 in control of PC differentiation and the ISC niche. Intestinal epithelial ErbB3 knockout caused precocious appearance of PCs as early as postnatal day 7, and substantially increased the number of mature PCs in adult mouse ileum. ErbB3 loss had no effect on other secretory lineages, but increased expression of the ISC marker Lgr5. ErbB3-null intestines had elevated levels of the Atoh1 transcription factor, which is required for secretory fate determination, while Atoh1(+) cells had reduced ErbB3, suggesting reciprocal negative regulation. ErbB3-null intestinal progenitor cells showed reduced activation of the PI3K-Akt and ERK MAPK pathways. Inhibiting these pathways in HT29 cells increased levels of ATOH1 and the PC marker LYZ. Conversely, ErbB3 activation suppressed LYZ and ATOH1 in a PI3K-dependent manner. Expansion of the PC compartment in ErbB3-null intestines was accompanied with elevated ER stress and inflammation markers, raising the possibility that negative regulation of PCs by ErbB3 is necessary to maintain homeostasis. Taken together, our data suggest that ErbB3 restricts PC numbers through PI3K-mediated suppression of Atoh1 levels leading to inhibition of PC differentiation, with important implications for regulation of the ISC niche.