1.感觉神经器官的发育 (Sensory Organ Development)
脊椎动物不同于其它动物的一个重要特征是它们身体前半部有大量丰富的旁侧感觉神经及其依附的感觉器官。这些器官包括嗅上皮，瞳仁，垂体，三叉神经器官，内耳，鳃弓神经器官，和侧线（鱼及两栖类特有）， 被誉为脊椎动物独有的进化标志。有趣的是，所有感觉器官的形态前体十分相似：它们都在外胚层特定的位置加厚形成基板。 经典胚胎学和近代发育生物学研究在过去的一百年间不断地争论这些感觉器官是否具有发育同源性。至本世纪，争论的焦点为：在脊椎动物发育的原肠胚期是否存在一个特定的前基板区，并由此分化出头部周围感觉神经系统。我们过去专注于内耳的发生研究，并于近两年初步揭开从前基板区到内耳命运决定的发育路 径。 我们将深入探讨前基板区是如何形成和分化的，并比较各种感觉器官形成机制的异同。
During the gastrulation, a distinct ectoderm region, the pre-placodal ectoderm (PPE), lies at rostral border of the neural ectoderm and gives rise to all ectodermal placodes, including the olfactory (of), lens (le), pituitary (pt), trigerminal (tg), epibranchial (eb), otic (op) and lateral line (ll) placodes. These placodes, the ectodermal thickenings by morphology, will develop into sensory organs unique to vertebrate. Although sensory placodes and the PPE were first described a long time ago (von Kupffer, 1891; Jacobson, 1963), it is still unclear how an embryo develops the PPE, how the PPE differentiates, and how a particular sensory organ obtains its identity. In search of answers to these questions, we will take advantage of an ectopic testing system that we have developed in zebrafish, to study how Bmp, Fgf and Wnt signaling pathways shape the PPE. We will test a hypothesis that PPE differentiation initiates at the rostra-caudal division of of/pt/le and ep/op/ll fields within the PPE, and plan to identify molecular basis of the process. Furthermore, we will study how differentiated PPE regions obtain unique sensory fates, ultimately providing foundation to regeneration of most sensory organs.
2. 听觉形成与再生（Hearing Development and Regeneration）
据统计，全球逾一亿人口患有各种各样听力丧失的疾病，其中大部分的听力损伤缘于内耳中听力功能细胞—毛细胞的损伤和无法再生或听觉神经萎缩，死亡。例如，老年性的听力衰退主因为内耳中毛细胞数量的明显减少：人类初生时每个内耳中具有1.6万-3万个毛细胞，但一经成熟，这些毛细胞在个体生长发育过程中不再增殖和再生，并因内在病变（遗传及后天获得的疾病，药物中毒等）和/或环境因素（污染，噪声，随声听等）而不断减少。由于与内耳相连的听觉神经分布和与毛细胞的配置十分精巧和复杂，所以耳蜗和干细胞移植均产生无法预期的并发症。因此目前治疗听力损伤最好的方法是希望在病人内耳的正确位置诱导毛细胞的适量再生，及与听觉神经建立准确的联系。研究毛细胞的发育机制，以及研究毛细胞损伤后再生障碍的机制，对于听觉及其康复的研究至关重要。我们实验室将毛细胞的发育和再生机理作为研究的长期目标，计划以斑马鱼为主要模式动物，用遗传，发育及经典胚胎生物学的方法开展研究工作。我们同时还将研究听觉神经的遗传发育，以探讨其再生可行性和如何与成熟毛细胞建立精准的联接。
It’s estimated that over 100 million of our population are suffering various types of hearing loss. Most hearing impairments in humans are due to damages of otic hair cells and/or their innervations, and our inability to regenerate these cells. For instance, age-related hearing loss is primarily due to a significant loss of hair cells because we are born with 16,000-30,000 hair cells in each ear but fail to regenerate any of them. Because of delicate innervations and wiring of otic nerves and hair cells, cochlear and stem cell implants lead to unexpected complications, the best cure of hearing impairments relies on hair cell regeneration in patients. Therefore, understanding the mechanism of hair cell development and unleashing inhibitory force of regeneration are center to hearing science. We will use two complementary approaches, i.e., using a mutant that never grows any otic hair cell and manipulating ectopically induced ears, to understand how the inner ear adopts hair cell fate. In addition, we will learn how the connection between hair cells and otic neurons is established.
代表性论文
1. Rotllant J., Liu D., Yan Y., Postlethwait J.H., Westerfield M. and Du S. , Sparc (Osteonectin) functions in morphogenesis of pharyngeal skeleton and inner ear , Matrix Biology , 2008 , 27: 561
2. Hans S., Christison J., Liu D. and Westerfield M. , Fgf-dependant otic induction requires competence provided by Foxi1 and Dlx3b , BMC Developmental Biology , 2007 , 7: 5
3. Yan Y-L., Willoughby J., Liu D., Crump J.G., Wilson C., Miller C.T., Singer A., Kimmel C., Westerfield M. and Postlethwait J.H. , A pair of Sox: distinct and overlapping functions of zebrafish Sox9 co-orthologs in craniofacial and pectoral fin development , Development , 2005 , 132: 1069
4. Hans S., Liu D. and Westerfield M. , Pax8 and Pax2a function synergistically in otic specification, downstream of the Foxi1 and Dlx3b transcription factors , Development , 2004 , 131: 5091
5. Liu D., Chu H., Maves L., Yan Y-L., Morcos P. A., Postlethwait J.H. and Westerfield M. , Fgf3 and Fgf8 dependent and independent transcription factors are required for otic placode specification , Development , 2003 , 130:2213
6. Yan Y-L., Miller C. T., Nissen R., Singer A., Liu D., Kirn A., Draper B., Willoughby J., Morcos P. A., Amsterdam A., Chung B., Westerfield M., Haffter P., Hopkins N., Kimmel C. and Postlethwait J. H. , Zebrafish sox9 gene required for cartilage morphogenesis , Development , 2002 , 129: 5065
7. Liu D., Chandy M., Lee S-K. Le Dréan Y., Xiong F., Lee J.W. and Hew C. L. , A zebrafish Ftz-F1 (fushi tarazu factor 1) homologue requires multiple sub-domains in the D and E regions for its transcriptional activity , The Journal of Biological Chemistry , 2000 , 275:16758
8. Liu D., Le Dréan Y., Ekker M., Xiong F. and Hew C. L. , Teleost FTZ-F1 homolog and its splicing variant determine the expression of salmon gonadotropin II beta gene , Molecular Endocrinology , 1997 , 11: 877
9. Le Dréan Y., Liu D., Wong A. O. L., Xiong F. and Hew C. L. 1996. , Steroidogenic factor1 and estradiol receptor act in synergism to regulate the expression of the salmon gonadotropin II beta subunit gene , Molecular Endocrinology , 1996 , 10: 217
10. Liu D., Xiong F. and Hew C. L. , Functional analysis of estrogen-responsive elements in Chinook salmon (Oncorhynchus tschawytscha) gonadotropin II beta subunit gene , Endocrinology , 1995 , 136: 3486
11. Xiong F., Liu D., Elsholtz H. P. and Hew C. L. , The Chinook salmon gonadotropin II beta subunit gene contains a strong minimal promoter with a proximal negative element , Molecular Endocrinology , 1994 , 8: 771
12. Xie Y., Liu D., Zou J., Li G. and Zhu Z. , Gene transfer via electroporation in fish , Aquaculture , 1993 , 111: 207
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