Department of Molecular and Cellular Physiology, School of Medicine, Stanford University, Stanford, CA, 94305, USA.
Research Unit Brain and Cognition, Laboratory of Biological Psychology, Social and Affective Neuroscience Research Group, Faculty of Psychology and Educational Sciences, KU Leuven, 3000, Leuven, Belgium.
Mol Autism. 2022 May 10;13(1):19. doi: 10.1186/s13229-022-00497-3.
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.
锌指结构域转录因子 Myt1l 与神经元特性密切相关，是唯一已知的神经元特异性且表达于所有神经元亚型的转录因子。我们发现 Myt1l 是一种强大的重编程因子，与神经前体细胞 bHLH 转录因子 Ascl1 结合，可诱导成纤维细胞向神经元命运分化。从分子水平上看，它抑制许多非神经元基因程序，这解释了其支持性作用，即与神经前体细胞 bHLH 转录激活因子结合诱导和保护神经元特性。此外，人类遗传学研究发现 MYT1L 突变导致智力障碍和自闭症谱系障碍，常伴有肥胖。
本研究生成并鉴定了 Myt1l 缺陷小鼠，并应用全面的、纵向的行为表型分析方法。
Myt1l 对于 24 小时后的存活是必需的，但对于整体脑组织结构并非必需。Myt1l 杂合子小鼠体重逐渐增加，并表现出多种行为改变。在幼鼠中，Myt1l 半合子缺失导致早期社会情感交流通过超声发声产生轻度改变。在成年期，Myt1l 杂合子小鼠由于习惯化学习受损而表现出过度活跃。尽管运动学习正常，但 Myt1l 杂合子小鼠的运动表现降低，可能是由于肌肉张力低下。虽然焦虑相关行为减少，但听觉惊跳反射增强，与对大声的敏感性增加一致。最后，Myt1l 半合子缺失对情景恐惧记忆检索有负面影响，而提示性恐惧记忆检索似乎完好无损。
在未来的研究中，可能会发现更多的表型，对直接的互惠社会互动行为进行详细的特征分析可能有助于揭示 Myt1l 半合子缺失对幼年和成年小鼠社会行为的影响。
Myt1l 半合子缺失小鼠的行为改变重现了携带杂合性 MYT1L 突变的人类中观察到的几种临床表型，因此是人类 MYT1L 综合征的一个有意义的模型。
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