The novel enterochromaffin marker Lmx1a regulates serotonin biosynthesis in enteroendocrine cell lineages downstream of Nkx2.2
The novel enterochromaffin marker Lmx1a regulates serotonin biosynthesis in enteroendocrine cell lineages downstream of Nkx2.2
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DOI：
10.1242/dev.130682
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发表时间：
2016-07-15
期刊：
影响因子：
4.6
通讯作者：
Sussel, Lori
中科院分区：
文献类型：
--
作者：
Gross, Stefanie;Garofalo, Diana C.;Sussel, Lori
肠内分泌细胞是人体内最大的内分泌系统，但对胚胎和成人肠内分泌细胞类型的特化知之甚少。我们分析了Nkx2.2及其功能结构域的阶段和细胞类型特异性缺失，以表征其在小鼠十二指肠和结肠肠内分泌细胞谱系发育和维持中的作用。尽管Nkx2.2在检查的所有阶段调节十二指肠中的肠内分泌细胞特化，但当从Ngn 3（+）祖细胞中删除或在成年十二指肠中删除时，它控制逐渐减少的肠内分泌细胞群体的分化。在胚胎发育期间，Nkx2.2调节除胃泌素和前胰高血糖素原以外的所有肠内分泌细胞类型。在Ngn 3+肠内分泌祖细胞的发育中，Nkx2.2不是神经肽Y和血管活性肠多肽的特化所需的，这表明这些细胞群的子集来自Nkx2.2非依赖性谱系。在成年十二指肠，Nkx2.2成为胆囊收缩素和分泌素产生的载体。在所有阶段和Nkx2.2突变的条件下，在十二指肠和结肠中，产生胡萝卜素的肠嗜铬细胞是最严重减少的肠内分泌谱系。我们确定转录因子Lmx 1a在肠嗜铬细胞中表达，并在Nkx2.2下游发挥作用。Lmx 1a缺陷小鼠Tph 1的表达减少，Tph 1是5-羟色胺生物合成的限速酶。这些数据阐明了Nkx2.2在肠内分泌群体的特化和稳态维持中的功能，并确定Lmx 1a是一种新型肠嗜铬细胞标记物，它对于5-羟色胺生物合成酶Tph 1的产生也至关重要。
Intestinal hormone-producing cells represent the largest endocrine system in the body, but remarkably little is known about enteroendocrine cell type specification in the embryo and adult. We analyzed stage- and cell type-specific deletions of Nkx2.2 and its functional domains in order to characterize its role in the development and maintenance of enteroendocrine cell lineages in the mouse duodenum and colon. Although Nkx2.2 regulates enteroendocrine cell specification in the duodenum at all stages examined, it controls the differentiation of progressively fewer enteroendocrine cell populations when deleted from Ngn3(+) progenitor cells or in the adult duodenum. During embryonic development Nkx2.2 regulates all enteroendocrine cell types, except gastrin and preproglucagon. In developing Ngn3+ enteroendocrine progenitor cells, Nkx2.2 is not required for the specification of neuropeptide Y and vasoactive intestinal polypeptide, indicating that a subset of these cell populations derive from an Nkx2.2-independent lineage. In adult duodenum, Nkx2.2 becomes dispensable for cholecystokinin and secretin production. In all stages and Nkx2.2 mutant conditions, serotonin-producing enterochromaffin cells were the most severely reduced enteroendocrine lineage in the duodenum and colon. We determined that the transcription factor Lmx1a is expressed in enterochromaffin cells and functions downstream of Nkx2.2. Lmx1a-deficient mice have reduced expression of Tph1, the rate-limiting enzyme for serotonin biosynthesis. These data clarify the function of Nkx2.2 in the specification and homeostatic maintenance of enteroendocrine populations, and identify Lmx1a as a novel enterochromaffin cell marker that is also essential for the production of the serotonin biosynthetic enzyme Tph1.