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Abstract
Zhu-Tokita-Takenouchi-Kim (ZTTK) syndrome, a rare congenital anomaly syndrome characterized by intellectual disability, brain malformation, facial dysmorphism, musculoskeletal abnormalities, and some visceral malformations is caused by de novo heterozygous mutations of the SON gene. The nuclear protein SON is involved in gene transcription and RNA splicing; however, the roles of SON in neural development remain undetermined. We investigated the effects of Son knockdown on neural development in mice and found that Son knockdown in neural progenitors resulted in defective migration during corticogenesis and reduced spine density on mature cortical neurons. The induction of human wild-type SON expression rescued these neural abnormalities, confirming that the abnormalities were caused by SON insufficiency. We also applied truncated SON proteins encoded by disease-associated mutant SON genes for rescue experiments and found that a truncated SON protein encoded by the most prevalent SON mutant found in ZTTK syndrome rescued the neural abnormalities while another much shorter mutant SON protein did not. These data indicate that SON insufficiency causes neuronal migration defects and dendritic spine abnormalities, which seem neuropathological bases of the neural symptoms of ZTTK syndrome. In addition, the results support that the neural abnormalities in ZTTK syndrome are caused by SON haploinsufficiency independent of the types of mutation that results in functional or dysfunctional proteins.
Highlights
Recent genetic studies identified 31 individuals exhibiting intellectual disability (ID) and/or developmental delay with de novo heterozygous mutations in SON, which was established as Zhu-Tokita-Takenouchi-Kim (ZTTK) syndrome [1,2,3,4,5,6]
We raised an antibody against mouse SON and found that it recognized a major band of approximately 260 kDa, which corresponds to the predicted size, and a few lower molecular weight bands upon Western blot analysis of mouse embryonic brain lysates (Fig. 1b)
The antibody worked well for immunohistochemistry as well, and we found that the most cells in the developing mouse brain at E15.5 expressed SON and that SON signals were especially conspicuous as nuclear speckles in presumptive migrating neuronal progenitors in the intermediate zone (IZ) and neurons in the cortical plate (Fig. 1d)
Summary
Recent genetic studies identified 31 individuals exhibiting intellectual disability (ID) and/or developmental delay with de novo heterozygous mutations in SON, which was established as Zhu-Tokita-Takenouchi-Kim (ZTTK) syndrome [1,2,3,4,5,6]. SON is a ubiquitously expressed and evolutionarily conserved gene in vertebrates and is located on the human chromosome region 21q22.11 [4]. It encodes the DNA- and RNA-binding protein SON, which functions in RNA splicing as well as gene repression [7,8,9,10,11,12,13]. We revealed through knockdown experiments in the developing mouse brain that Son insufficiency caused neuronal migration abnormalities and reduced spine density. Rescue experiments that induced the expression of human wild-type SON protein and truncated SON proteins encoded by disease-associated mutant SON genes provided further information relevant to the pathophysiology of ZTTK syndrome
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