A Highly Conserved Shh Enhancer Coordinates Hypothalamic and Craniofacial Development.
A Highly Conserved Shh Enhancer Coordinates Hypothalamic and Craniofacial Development.
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DOI：
10.3389/fcell.2021.595744
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发表时间：
2021
影响因子：
5.5
通讯作者：
Hill RE
中科院分区：
文献类型：
--
作者：
Crane-Smith Z;Schoenebeck J;Graham KA;Devenney PS;Rose L;Ditzell M;Anderson E;Thomson JI;Klenin N;Kurrasch DM;Lettice LA;Hill RE
增强子在进化过程中是保守的，它们调节着在分类学类别中共有的特征。在这里，在小鼠中高度保守的Shh增强子SBE 2（Shh脑增强子2）的缺失显着降低了胚胎脑内的Shh表达，特别是在吻侧间脑;然而，没有观察到异常的解剖表型。随后鉴定了可能介导低水平表达的二级增强子活性。相反，当SBE 2缺失与Shh无效等位基因交叉时，大脑和颅面发育被破坏;因此，将SBE 2调节的Shh表达与多种缺陷联系起来，并进一步研究不同水平的Shh对胚胎发生的影响。下丘脑的发展，从吻间脑，被中断沿着沿前后（AP）和背腹（DV）轴。DV图案化基因的表达和随后的神经元群体诱导对Shh表达水平特别敏感，证明了Shh的新形态发生背景。SBE 2的作用，这是突出的DV基因表达，是逐步表达的Shh以上的第二个增强子的最小活性，确保在区域特异性的方式Shh的必要水平。我们还表明，间脑中的低Shh水平扰乱了邻近的颅面发育，包括沿颅底和内脏颅的骨骼沿着的中外侧图案。因此，SBE 2有助于下丘脑形态发生，并确保与相邻中线颅骨的形成协调，随后保护神经组织。
Enhancers that are conserved deep in evolutionary time regulate characteristics held in common across taxonomic classes. Here, deletion of the highly conserved Shh enhancer SBE2 (Shh brain enhancer 2) in mouse markedly reduced Shh expression within the embryonic brain specifically in the rostral diencephalon; however, no abnormal anatomical phenotype was observed. Secondary enhancer activity was subsequently identified which likely mediates low levels of expression. In contrast, when crossing the SBE2 deletion with the Shh null allele, brain and craniofacial development were disrupted; thus, linking SBE2 regulated Shh expression to multiple defects and further enabling the study of the effects of differing levels of Shh on embryogenesis. Development of the hypothalamus, derived from the rostral diencephalon, was disrupted along both the anterior-posterior (AP) and the dorsal-ventral (DV) axes. Expression of DV patterning genes and subsequent neuronal population induction were particularly sensitive to Shh expression levels, demonstrating a novel morphogenic context for Shh. The role of SBE2, which is highlighted by DV gene expression, is to step-up expression of Shh above the minimal activity of the second enhancer, ensuring the necessary levels of Shh in a regional-specific manner. We also show that low Shh levels in the diencephalon disrupted neighbouring craniofacial development, including mediolateral patterning of the bones along the cranial floor and viscerocranium. Thus, SBE2 contributes to hypothalamic morphogenesis and ensures there is coordination with the formation of the adjacent midline cranial bones that subsequently protect the neural tissue.
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影响因子：
9.8
作者：
Dessaud E;Ribes V;Balaskas N;Yang LL;Pierani A;Kicheva A;Novitch BG;Briscoe J;Sasai N
通讯作者：
Sasai N
DOI：
10.1242/dev.108480
发表时间：
2014-10
期刊：
Development (Cambridge, England)
影响因子：
--
作者：
Anderson E;Devenney PS;Hill RE;Lettice LA
通讯作者：
Lettice LA
影响因子：
4.6
作者：
Jeong, YS;El-Jaick, K;Epstein, DJ
通讯作者：
Epstein, DJ
影响因子：
4.5
作者：
Kim, Namhee;Park, Chungoo;Song, Mi-Ryoung
通讯作者：
Song, Mi-Ryoung
影响因子：
30.8
作者：
Letelier, Joaquin;de la Calle-Mustienes, Elisa;Luis Gomez-Skarmeta, Jose
通讯作者：
Luis Gomez-Skarmeta, Jose