Hapln1a is required for connexin43-dependent growth and patterning in the regenerating fin skeleton.
Hapln1a is required for connexin43-dependent growth and patterning in the regenerating fin skeleton.
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DOI：
10.1371/journal.pone.0088574
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发表时间：
2014
期刊：
影响因子：
3.7
通讯作者：
Iovine MK
中科院分区：
文献类型：
--
作者：
Govindan J;Iovine MK
细胞间的通讯，促进小的代谢物，离子和第二信使的交换，通过称为间隙连接的水性蛋白质通道进行。连接蛋白（cx）是缝隙连接通道的亚单位。斑马鱼cx43突变产生短鳍（sof b123）表型，其特征是由于骨鳍条的节段长度减少和细胞增殖减少而导致的短鳍。我们实验室先前建立的结果表明，Cx43在骨骼形态发生过程中起着调节细胞增殖（生长）和关节形成（模式化）的双重作用。在这项研究中，我们表明，Hapln 1a（Hybryonan和蛋白聚糖连接蛋白1a）的cx43下游的功能。Hapln 1a属于连接蛋白家族，其通过连接透明质酸和蛋白聚糖的聚集体在稳定ECM中起重要作用。通过原位杂交和定量RT-PCR方法验证了hapln 1a在cx43下游表达。此外，在不同时间点的原位杂交显示，hapln 1a表达高峰在截肢后3天。hapln 1a的表达位于内侧间充质和外侧骨骼前体细胞中。此外，吗啉介导的hapln 1a敲低导致鳍再生长度减少，骨节长度减少和细胞增殖减少，重现了cx43敲低的所有表型。此外，Hapln 1a敲除鳍中的透明质酸（HA）水平显著降低，证明了Hapln 1a在稳定ECM中的重要性。尝试将hapln 1a放置在我们先前定义的cx43-sema 3d通路中表明hapln 1a在一个平行的遗传通路中起作用。总的来说，我们的数据表明，Cx43介导独立的Sema 3d和Hapln 1a途径，以协调骨骼的生长和图案。
Cell–cell communication, facilitating the exchange of small metabolites, ions and second messengers, takes place via aqueous proteinaceous channels called gap junctions. Connexins (cx) are the subunits of a gap junction channel. Mutations in zebrafish cx43 produces the short fin (sof b123) phenotype and is characterized by short fins due to reduced segment length of the bony fin rays and reduced cell proliferation. Previously established results from our lab demonstrate that Cx43 plays a dual role regulating both cell proliferation (growth) and joint formation (patterning) during the process of skeletal morphogenesis. In this study, we show that Hapln1a (Hyaluronan and Proteoglycan Link Protein 1a) functions downstream of cx43. Hapln1a belongs to the family of link proteins that play an important role in stabilizing the ECM by linking the aggregates of hyaluronan and proteoglycans. We validated that hapln1a is expressed downstream of cx43 by in situ hybridization and quantitative RT-PCR methods. Moreover, in situ hybridization at different time points revealed that hapln1a expression peaks at 3 days post amputation. Expression of hapln1a is located in the medial mesenchyme and the in the lateral skeletal precursor cells. Furthermore, morpholino mediated knock-down of hapln1a resulted in reduced fin regenerate length, reduced bony segment length and reduced cell proliferation, recapitulating all the phenotypes of cx43 knock-down. Moreover, Hyaluronic Acid (HA) levels are dramatically reduced in hapln1a knock-down fins, attesting the importance of Hapln1a in stabilizing the ECM. Attempts to place hapln1a in our previously defined cx43–sema3d pathway suggest that hapln1a functions in a parallel genetic pathway. Collectively, our data suggest that Cx43 mediates independent Sema3d and Hapln1a pathways in order to coordinate skeletal growth and patterning.
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