BBS genes are involved in accelerated proliferation and early differentiation of BBS-related tissues

IF 2.2 3区生物学 Q4 CELL BIOLOGY Differentiation Pub Date : 2024-01-01 DOI:10.1016/j.diff.2024.100745

Avital Horwitz , Noa Levi-Carmel , Olga Shnaider , Ruth Birk

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Abstract

Bardet-Biedl syndrome (BBS) is an inherited disorder primarily ciliopathy with pleiotropic multi-systemic phenotypic involvement, including adipose, nerve, retinal, kidney, Etc. Consequently, it is characterized by obesity, cognitive impairment and retinal, kidney and cutaneous abnormalities. Initial studies, including ours have shown that BBS genes play a role in the early developmental stages of adipocytes and β-cells. However, this role in other BBS-related tissues is unknown.

We investigated BBS genes involvement in the proliferation and early differentiation of different BBS cell types.

The involvement of BBS genes in cellular proliferation were studied in seven in-vitro and transgenic cell models; keratinocytes (hHaCaT) and Ras-transfected keratinocytes (Ras-hHaCaT), neuronal cell lines (hSH-SY5Y and rPC-12), silenced BBS4 neural cell lines (siBbs4 hSH-SY5Y and siBbs4 rPC-12), adipocytes (m3T3L1), and ex-vivo transformed B-cells obtain from BBS4 patients, using molecular and biochemical methodologies.

RashHaCaT cells showed an accelerated proliferation rate in parallel to significant reduction in the transcript levels of BBS1, 2, and 4. BBS1, 2, and 4 transcripts linked with hHaCaT cell cycle arrest (G1 phase) using both chemical (CDK4 inhibitor) and serum deprivation methodologies. Adipocyte (m3T3-L1) Bbs1, 2 and 4 transcript levels corresponded to the cell cycle phase (CDK4 inhibitor and serum deprivation). SiBBS4 hSH-SY5Y cells exhibited early cell proliferation and differentiation (wound healing assay) rates. SiBbs4 rPC-12 models exhibited significant proliferation and differentiation rate corresponding to Nestin expression levels. BBS4 patients-transformed B-cells exhibited an accelerated proliferation rate (LPS-induced methodology).

In conclusions, the BBS4 gene plays a significant, similar and global role in the cellular proliferation of various BBS related tissues. These results highlight the universal role of the BBS gene in the cell cycle, and further deepen the knowledge of the mechanisms underlying the development of BBS.

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BBS 基因参与 BBS 相关组织的加速增殖和早期分化

巴尔德-比德尔综合征（Bardet-Biedl Syndrome，BBS）是一种以纤毛虫病为主的遗传性疾病，多系统表型受累，包括脂肪、神经、视网膜、肾脏等。因此，该病的特征是肥胖、认知障碍以及视网膜、肾脏和皮肤异常。包括我们在内的初步研究表明，BBS 基因在脂肪细胞和 β 细胞的早期发育阶段发挥作用。我们研究了 BBS 基因参与不同 BBS 细胞类型增殖和早期分化的情况。我们在七个体外和转基因细胞模型中研究了 BBS 基因参与细胞增殖的情况；使用分子和生化方法研究了七种体外和转基因细胞模型：角质形成细胞（hHaCaT）和 Ras 转染角质形成细胞（Ras-hHaCaT）、神经细胞系（hSH-SY5Y 和 rPC-12）、沉默 BBS4 神经细胞系（siBbs4 hSH-SY5Y 和 siBbs4 rPC-12）、脂肪细胞（m3T3L1）以及从 BBS4 患者体内获得的体外转化 B 细胞。RashHaCaT 细胞的增殖速度加快，同时 BBS1、2 和 4 的转录水平显著降低。利用化学方法（CDK4 抑制剂）和血清剥夺法，BBS1、2 和 4 转录本与 hHaCaT 细胞周期停滞（G1 期）有关。脂肪细胞（m3T3-L1）的 Bbs1、2 和 4 转录本水平与细胞周期阶段（CDK4 抑制剂和血清剥夺）相对应。SiBBS4 hSH-SY5Y 细胞表现出早期细胞增殖和分化（伤口愈合试验）率。SiBbs4 rPC-12 模型表现出与 Nestin 表达水平相对应的显著增殖和分化率。总之，BBS4 基因在各种 BBS 相关组织的细胞增殖中发挥着重要、相似和全球性的作用。这些结果凸显了 BBS 基因在细胞周期中的普遍作用，并进一步加深了人们对 BBS 发病机制的认识。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

Differentiation 生物-发育生物学

CiteScore

4.10

自引率

3.40%

发文量

审稿时长

51 days

期刊介绍： Differentiation is a multidisciplinary journal dealing with topics relating to cell differentiation, development, cellular structure and function, and cancer. Differentiation of eukaryotes at the molecular level and the use of transgenic and targeted mutagenesis approaches to problems of differentiation are of particular interest to the journal. The journal will publish full-length articles containing original work in any of these areas. We will also publish reviews and commentaries on topics of current interest. The principal subject areas the journal covers are: • embryonic patterning and organogenesis • human development and congenital malformation • mechanisms of cell lineage commitment • tissue homeostasis and oncogenic transformation • establishment of cellular polarity • stem cell differentiation • cell reprogramming mechanisms • stability of the differentiated state • cell and tissue interactions in vivo and in vitro • signal transduction pathways in development and differentiation • carcinogenesis and cancer • mechanisms involved in cell growth and division especially relating to cancer • differentiation in regeneration and ageing • therapeutic applications of differentiation processes.