The Ldb1 transcriptional co-regulator is required for establishment and maintenance of the pancreatic endocrine lineage.
The Ldb1 transcriptional co-regulator is required for establishment and maintenance of the pancreatic endocrine lineage.
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DOI：
10.1096/fj.202200410r
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发表时间：
2022-08
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影响因子：
--
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胰岛细胞的发育受转录因子（TF）的调节，这些转录因子介导胚胎祖细胞向成熟内分泌细胞的分化。我们实验室和其他人的先前研究表明，富含胰岛的TF，Islet-1（Isl 1），与广泛表达的转录辅助调节因子Ldb 1相互作用，以调节胰岛细胞成熟和出生后功能（胚胎日（E）18.5）。然而，Ldb 1在发育中的胰腺中先于Isl 1表达，特别是在由Pdx 1标记的多能祖细胞（MPC）和表达神经生成素-3（Ngn 3）的内分泌祖细胞（EP）中。MPC产生内分泌和外分泌胰腺，而Ngn 3 + EP指定胰岛内分泌细胞。我们假设Ldb 1是MPC和EP人群在发育过程中影响胰岛外观和功能的祖细胞身份所必需的。为了测试这一点，我们产生了一个全胰腺Ldb 1基因敲除，称为Ldb 1 β Panc，并观察到严重的发育和出生后胰腺缺陷，包括混乱的祖细胞池，Ngn 3表达的EP，Pdx 1HI β细胞和早期激素+细胞的显着减少。Ldb 1型胰腺癌新生儿表现为严重的高血糖、低胰岛素血症，胰岛激素表达显著降低，但总胰腺质量无变化。这支持Ldb 1的内分泌特异性作用。考虑到这一点，我们还开发了一种内分泌富集的Ldb 1损失模型，称为Ldb 1内分泌Endo。我们在该模型中观察到类似的功能障碍，以及胰岛身份标志物的丢失。通过体外和体内染色质免疫沉淀实验，我们发现Ldb 1占据了Pdx 1和Ngn 3启动子的关键结构域。我们的研究结果提供了对内分泌细胞分化的新调节的见解，这可能对改善基于细胞的糖尿病治疗至关重要。
Pancreatic islet cell development is regulated by transcription factors (TFs) that mediate embryonic progenitor differentiation toward mature endocrine cells. Prior studies from our lab and others showed that the islet-enriched TF, Islet-1 (Isl1), interacts with the broadly-expressed transcriptional co-regulator, Ldb1, to regulate islet cell maturation and postnatal function (by embryonic day (E)18.5). However, Ldb1 is expressed in the developing pancreas prior to Isl1 expression, notably in multipotent progenitor cells (MPCs) marked by Pdx1, and endocrine progenitors (EPs) expressing Neurogenin-3 (Ngn3). MPCs give rise to the endocrine and exocrine pancreas, while Ngn3+ EPs specify pancreatic islet endocrine cells. We hypothesized that Ldb1 is required for progenitor identity in MPC and EP populations during development to impact islet appearance and function. To test this, we generated a whole-pancreas Ldb1 knockout, termed Ldb1∆Panc, and observed severe developmental and postnatal pancreas defects including disorganized progenitor pools, a significant reduction of Ngn3-expressing EPs, Pdx1HI β-cells, and early hormone+ cells. Ldb1∆Panc neonates presented with severe hyperglycemia, hypoinsulinemia, and drastically reduced hormone expression in islets, yet no change in total pancreas mass. This supports endocrine-specific actions of Ldb1. Considering this, we also developed an endocrine-enriched model of Ldb1 loss, termed Ldb1∆Endo. We observed similar dysglycemia in this model, as well as a loss of islet identity markers. Through in vitro and in vivo chromatin immunoprecipitation experiments, we found that Ldb1 occupies key Pdx1 and Ngn3 promoter domains. Our findings provide insight into novel regulation of endocrine cell differentiation that may be vital toward improving cell-based diabetes therapies.
影响因子：
2.2
作者：
Ogihara T;Vanderford NL;Maier B;Stein RW;Mirmira RG
通讯作者：
Mirmira RG
影响因子：
7.7
作者：
Cox AR;Kushner JA
通讯作者：
Kushner JA