Myt1l haploinsufficiency leads to obesity and multifaceted behavioral alterations in mice.
Myt1l haploinsufficiency leads to obesity and multifaceted behavioral alterations in mice.
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DOI：
10.1186/s13229-022-00497-3
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发表时间：
2022-05-10
期刊：
影响因子：
6.2
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中科院分区：
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--
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含有转录因子Myt1l的锌指结构域与神经元的特性密切相关，是目前已知的唯一一种神经元特异性的转录因子，在所有神经元亚型中都有表达。我们发现Myt1l是一种强大的重编程因子，与原神经bHLH因子Ascl1相结合，可以诱导成纤维细胞中的神经元命运。在分子上，我们发现它抑制了许多非神经性基因程序，解释了它与神经性bHLH转录激活剂结合在一起对诱导和保护神经元身份的支持作用。此外，人类遗传学研究发现，Myt1基因突变会导致智力残疾和自闭症谱系障碍，通常伴随着肥胖。在这里，我们培育了Myt1l缺陷小鼠并对其进行了鉴定。一种全面的、纵向的行为表型方法被应用。Myt1对存活超过24小时是必需的，但对整个组织学脑组织来说不是必需的。Myt11杂合子小鼠变得越来越超重，并表现出多方面的行为变化。在小鼠幼鼠中，Myt1单倍体不足通过超声波发声导致早期社会情感交流的轻微变化。成年后，Myt11杂合子小鼠由于习惯性学习受损而表现出多动。Myt11杂合子小鼠尽管运动学习完好，但运动能力下降，可能是由于肌肉张力低下所致。虽然焦虑相关的行为减少了，但听觉惊吓反应增强了，这与对响亮的声音更高的敏感度一致。最后，Myt1单倍体不足对背景恐惧记忆提取有负面影响，而线索恐惧记忆提取似乎是完整的。在未来的研究中，可能会确定更多的表型，并对直接互惠的社会相互作用行为进行详细的表征，这可能有助于揭示Myt1单倍体不足对幼年和成年小鼠社会行为的影响。Myt1单倍体缺陷小鼠的行为改变概括了在携带Myt1杂合突变的人类中观察到的几种临床表型，从而成为人类Myt1综合征的信息模型。网上版载有补充材料，可在10.1186/s13229-022-00497-3查阅。
The zinc finger domain containing transcription factor Myt1l is tightly associated with neuronal identity and is the only transcription factor known that is both neuron-specific and expressed in all neuronal subtypes. We identified Myt1l as a powerful reprogramming factor that, in combination with the proneural bHLH factor Ascl1, could induce neuronal fate in fibroblasts. Molecularly, we found it to repress many non-neuronal gene programs, explaining its supportive role to induce and safeguard neuronal identity in combination with proneural bHLH transcriptional activators. Moreover, human genetics studies found MYT1L mutations to cause intellectual disability and autism spectrum disorder often coupled with obesity. Here, we generated and characterized Myt1l-deficient mice. A comprehensive, longitudinal behavioral phenotyping approach was applied. Myt1l was necessary for survival beyond 24 h but not for overall histological brain organization. Myt1l heterozygous mice became increasingly overweight and exhibited multifaceted behavioral alterations. In mouse pups, Myt1l haploinsufficiency caused mild alterations in early socio-affective communication through ultrasonic vocalizations. In adulthood, Myt1l heterozygous mice displayed hyperactivity due to impaired habituation learning. Motor performance was reduced in Myt1l heterozygous mice despite intact motor learning, possibly due to muscular hypotonia. While anxiety-related behavior was reduced, acoustic startle reactivity was enhanced, in line with higher sensitivity to loud sound. Finally, Myt1l haploinsufficiency had a negative impact on contextual fear memory retrieval, while cued fear memory retrieval appeared to be intact. In future studies, additional phenotypes might be identified and a detailed characterization of direct reciprocal social interaction behavior might help to reveal effects of Myt1l haploinsufficiency on social behavior in juvenile and adult mice. Behavioral alterations in Myt1l haploinsufficient mice recapitulate several clinical phenotypes observed in humans carrying heterozygous MYT1L mutations and thus serve as an informative model of the human MYT1L syndrome. The online version contains supplementary material available at 10.1186/s13229-022-00497-3.
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影响因子：
4.5
作者：
Blanchet P;Bebin M;Bruet S;Cooper GM;Thompson ML;Duban-Bedu B;Gerard B;Piton A;Suckno S;Deshpande C;Clowes V;Vogt J;Turnpenny P;Williamson MP;Alembik Y;Clinical Sequencing Exploratory Research Study Consortium;Deciphering Developmental Disorders Consortium;Glasgow E;McNeill A
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McNeill A
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2
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Makitie, Outi
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影响因子：
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作者：
Li, W.;Wang, X.;Lv, L. -X.
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Lv, L. -X.
影响因子：
9.8
作者：
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Schreiner, Christoph E.
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作者：
De Rocker, Nina;Vergult, Sarah;Menten, Bjoern
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