Sex-Linked Growth Disorder and Aberrant Pituitary Gene Expression in Nestin-Cre-Mediated Egr1 Conditional Knockout Mice.
Sex-Linked Growth Disorder and Aberrant Pituitary Gene Expression in Nestin-Cre-Mediated Egr1 Conditional Knockout Mice.
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在没有Egr 1基因的小鼠和携带Nestin-Cre驱动程序的小鼠中观察到生长激素水平降低。目前尚不清楚为什么这两个品系的小鼠具有相似的表型，以及垂体中激素产生的失调是否通过相同的机制发生。先前的研究显示了关于Nestin-Cre在垂体中驱动基因敲除的有效性的相互矛盾的结果。在这项研究中，我们发现，虽然Nestin-Cre驱动程序成功地去除了神经元谱系细胞中的Egr 1表达，但它并没有有效地将其从垂体的所有部分中去除。此外，Nestin-Cre驱动程序单独导致小鼠生长异常，并影响垂体中与生长因子相关的基因表达。在表现出这些生长和基因表达异常的小鼠中也观察到性别差异，雌性小鼠对Nestin-Cre的存在和Egr 1的缺失更敏感。总的来说，这项研究强调了Nestin-Cre驱动程序在从垂体细胞中去除Egr 1方面的局限性，并深入了解了Nestin-Cre对生长和基因表达的影响，特别是与性别差异有关的影响。调节激素释放的基因对维持新陈代谢和能量平衡至关重要。Egr 1编码一种调节激素产生和释放的转录因子，据报道，Egr 1基因敲除小鼠的生长激素减少。在Nestin-Cre小鼠中也观察到生长激素的减少，这是一种经常用于研究神经系统的模型。目前，还不清楚Egr 1丢失或Nestin-Cre驱动程序如何破坏垂体基因表达。在这里，我们比较了Nestin-Cre介导的Egr 1条件性基因敲除（Egr 1cKO）小鼠的生长曲线和垂体基因表达谱与其对照组。在Nestin-Cre和Egr 1cKO小鼠中均观察到体重减轻，Egr 1缺失对雌性小鼠的影响略大于雄性小鼠。RNA-seq数据分析显示，在Nestin-Cre介导的Egr 1条件性敲除小鼠中，性别相关差异被放大。此外，在雄性小鼠中，Egr 1cKO对垂体基因表达的影响可能被Nestin-Cre驱动程序所覆盖。与Nestin-Cre驱动相关的差异表达基因显著富集与生长因子活性和结合相关的基因。总之，我们的研究结果表明，Nestin-Cre和神经元细胞系中Egr 1的缺失对垂体基因表达具有明显的性别特异性影响。
Reduced growth hormone levels were observed in mice without the Egr1 gene and mice carrying a Nestin-Cre driver. It remains unknown why these two strains of mice share a similar phenotype and whether the dysregulation of hormone production in the pituitary occurs via the same mechanism. Previous studies have shown conflicting results regarding the effectiveness of Nestin-Cre in driving gene knockout in the pituitary. In this study, we found that while the Nestin-Cre driver successfully removed Egr1 expression in neuronal lineage cells, it did not effectively remove it from all sections of the pituitary. Moreover, the Nestin-Cre driver alone caused growth abnormalities in the mice and influenced the expression of genes related to growth factors in the pituitary. Sex differences were also observed in the mice that exhibited these growth and gene expression abnormalities, with female mice being more sensitive to the presence of Nestin-Cre and the loss of Egr1. Overall, this study highlights the limitations of the Nestin-Cre driver in removing Egr1 from pituitary cells and provides insights into the impact of Nestin-Cre on growth and gene expression, particularly in relation to sex differences. Genes that regulate hormone release are essential for maintaining metabolism and energy balance. Egr1 encodes a transcription factor that regulates hormone production and release, and a decreased in growth hormones has been reported in Egr1 knockout mice. A reduction in growth hormones has also been observed in Nestin-Cre mice, a model frequently used to study the nervous system. Currently, it is unknown how Egr1 loss or the Nestin-Cre driver disrupt pituitary gene expression. Here, we compared the growth curves and pituitary gene expression profiles of Nestin-Cre-mediated Egr1 conditional knockout (Egr1cKO) mice with those of their controls. Reduced body weight was observed in both the Nestin-Cre and Egr1cKO mice, and the loss of Egr1 had a slightly more severe impact on female mice than on male mice. RNA-seq data analyses revealed that the sex-related differences were amplified in the Nestin-Cre-mediated Egr1 conditional knockout mice. Additionally, in the male mice, the influence of Egr1cKO on pituitary gene expression may be overridden by the Nestin-Cre driver. Differentially expressed genes associated with the Nestin-Cre driver were significantly enriched for genes related to growth factor activity and binding. Altogether, our results demonstrate that Nestin-Cre and the loss of Egr1 in the neuronal cell lineage have distinct impacts on pituitary gene expression in a sex-specific manner.
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