Six1 Regulates Mouse Incisor Development by Promoting Dlx1/2/5 Expression.

Journal of dental research Pub Date : 2024-09-01 Epub Date: 2024-08-05 DOI:10.1177/00220345241256286
S Y Luo, S Wang, Z X Liu, Q Bian, X D Wang
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Abstract

Tooth development is a complex process orchestrated by intricate gene regulatory networks, involving both odontogenic epithelium and ectomesenchyme. Six1, a pivotal transcription factor (TF), is involved in the development of the lower incisor. However, its precise role during incisor development and the molecular mechanisms underpinning its regulatory functions remain poorly understood. This study employs Six1 deletion mouse models to elucidate the critical regulatory role of Six1 in governing dental mesenchyme development. By performing single-cell RNA sequencing, we constructed a comprehensive transcriptome atlas of tooth germ development from the bud to bell stage. Our analyses suggest that the dental follicle and the dental papilla (DP) are differentiated from dental ectomesenchyme (DEM) and identify the key TFs underlying these distinct states. Notably, we show that Dlx1, Dlx2, and Dlx5 (Dlx1/2/5) may function as the key TFs that promote the formation of DP. We further show that the deletion of Six1 perturbs dental mesenchyme development by impeding the transitions from DEM to DP states. Importantly, SIX1 directly binds to the promoters of Dlx1/2/5 to promote their co-expression, which subsequently leads to widespread epigenetic and transcriptional remodeling. In summary, our findings unveil Six1's indispensable role in incisor development, offering key insights into TF-driven regulatory networks that govern dental mesenchyme cell fate transitions during tooth development.

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Six1 通过促进 Dlx1/2/5 的表达调控小鼠门齿的发育
牙齿发育是一个复杂的过程,由错综复杂的基因调控网络协调,涉及牙源性上皮和外胚层。Six1是一种关键的转录因子(TF),参与了下切牙的发育。然而,人们对它在门牙发育过程中的确切作用及其调控功能的分子机制仍然知之甚少。本研究利用Six1缺失小鼠模型来阐明Six1在牙齿间质发育过程中的关键调控作用。通过进行单细胞 RNA 测序,我们构建了一个全面的转录组图谱,该图谱涵盖了从萌芽到钟期的牙胚发育过程。我们的分析表明,牙泡和牙乳头(DP)是从牙外胚层(DEM)分化出来的,并确定了这些不同状态下的关键 TFs。值得注意的是,我们发现 Dlx1、Dlx2 和 Dlx5(Dlx1/2/5)可能是促进 DP 形成的关键 TF。我们进一步发现,Six1的缺失会阻碍牙间质从DEM向DP状态的转变,从而扰乱牙间质的发育。重要的是,SIX1直接与Dlx1/2/5的启动子结合,促进它们的共同表达,随后导致广泛的表观遗传和转录重塑。总之,我们的研究结果揭示了SIX1在门牙发育过程中不可或缺的作用,为了解牙齿发育过程中牙间质细胞命运转换的TF驱动调控网络提供了重要信息。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
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