Molecular mechanisms that regulate auditory hair-cell differentiation in the mammalian cochlea

Mechanosensory hair cells of the vertebrate cochlea offer an excellent developmental system to study cell-fate specification, and to gain insight into the many human neurological deficits which result in a hearing loss, by affecting primarily the hair cells. Therefore, there is great interest in studying the molecular mechanisms that regulate their specification and differentiation. Recent studies, based mostly on loss-of-function experiments that target the role of Notch signaling and basic helix-loop-helix genes in inner-ear development have indicated that they can regulate mechanosensory hair cell-fate specification and their initial differentiation.     

Molecular mechanisms of testosterone action in spermatogenesis

Testosterone is required for the maturation of male germ cells, the production of sperm and thus male fertility. However, the mechanisms by which testosterone regulates spermatogenic processes have not been well defined. In this review, classical and non-classical pathways of testosterone signaling in the Sertoli cells of the testis are discussed in relation to testosterone-regulated processes that are required for spermatogenesis.     

Molecular mechanisms of thymocyte differentiation

A review of the main molecular events occurring during differentiation of T-lymphocytes in the thymus: T-cell specialization of early intrathymic precursors, formation and expression of antigen receptor, formation of antigen recognizing cell repertoire, and alpha beta/gamma beta- and CD4/CD8-commitment. The mechanisms of glucocorticoid-induced apoptosis of thymocytes and its blockade during antigen-dependent activation are considered. A special attention is paid to the analysis of intracellular signals underlying the clonal selection of thymocytes.     

Molecular mechanisms of mechanotransduction in mammalian sensory neurons

The somatosensory system mediates fundamental physiological functions, including the senses of touch, pain and proprioception. This variety of functions is matched by a diverse array of mechanosensory neurons that respond to force in a specific fashion. Mechanotransduction begins at the sensory nerve endings, which rapidly transform mechanical forces into electrical signals. Progress has been made in establishing the functional properties of mechanoreceptors, but it has been remarkably difficult to characterize mechanotranducer channels at the molecular level. However, in the past few years, new functional assays have provided insights into the basic properties and molecular identity of mechanotransducer channels in mammalian sensory neurons. The recent identification of novel families of proteins as mechanosensing molecules will undoubtedly accelerate our understanding of mechanotransduction mechanisms in mammalian somatosensation.     

哺乳动物细胞mRNA剪接调控的分子机制

mRNA的可变剪接是指一个单一的mRNA前体(pre-mRNA)经过不同的剪接加工方式生成多种mRNA变异体(variants)的过程,这些变异体最终可以编码合成具有不同结构和功能的蛋白质。在过去的10多年中,大量数据表明,可变剪接是增加转录组和蛋白质组多样性的重要资源,也是调控哺乳动物细胞基因表达的重要步骤。可变剪接具有高度的组织与发育阶段特异性,并受到外界信号的控制。剪接调控的紊乱与疾病的发生发展密切相关。该文将对哺乳动物细胞mRNA剪接调控的分子机制进行阐述。     

哺乳动物精子体外发生

精子的发生是一个高度复杂而有序的过程 ,涉及到细胞的增殖和分化。体外培养生精细胞在近年来取得了较大进展 ,建立了睾丸组织培养、曲精细管小段培养、支持细胞 生精细胞共培养及藻酸钙胶囊包裹培养等方法。建立生精细胞体外培养模型有助于 :(1)研究精子发生的调控机制 ;(2 )直接对雄性生殖细胞进行遗传修饰 ;(3)用于辅助生育技术 ,治疗精子发生阻滞的患者。如何改善培养条件 ,进一步提高生殖细胞的存活、分化、增殖效率 ,是使哺乳动物体外精子发生发展成为一项适用性较强的技术所必须解决的问题。     

Involvement of cyclins in mammalian spermatogenesis

Human promyelocytic leukemia HL-60 cells represent an in vitro model of acute promyelocytic leukemia (APL), and are inducible to terminally differentiate into morphologically mature granulocytes by incubation with all trans retinoic acid (ATRA). Lysosomal glycohydrolases are involved in the changes of the membrane surface proteins’ glycosylation, linked to the metastatic progression potential of neoplastic cells. In particular, it has been demonstrated that the Asn-linked glucidic residues were directly responsible for the metastatic potential, and it is known that the glycohydrolase α-d-mannosidase specifically hydrolyze the Asn-linked oligosaccharides. In this report, we present an in vitro study on the ATRA effects on lysosomal glycohydrolases expression and the eventual relationship with the retinoic acid-induced differentiation of HL-60 cells. We have investigated two highly expressed lysosomal glycohydrolases, namely β-d-hexosaminidase and α-d-mannosidase, and showed that they were differently affected by ATRA differentiating action. In particular, due to the specific action on Asn-linked oligosaccharides, we tested α-d-mannosidase enzymatic activity and observed that it was dramatically decreased after ATRA incubation, indicating a relationship with the differentiation state of the cells. These observations may directly be linked with the loss of metastatic progession of differentiated HL-60.     

The local control of mammalian spermatogenesis

Summary Investigations of the ultrastructure of mammalian spermatogenesis have revealed intercellular bridges in all cell generations of the germinal epithelium. Desmosomes connect Sertoli cells with associated Sertoli cells (Sertoli cell — Sertoli cell junction) and with adjacent cells of the germinal epithelium. To provide evidence for the different types of cell connections in all developmental stages of spermatogenesis the various cell generations had to be worked out. This was achieved by considering the morphology of the nuclei and the relation of the cells to cell associations of the spermatogenic cycle in which they have been observed.These observations led us to a hypothesis explaining the local control of the spermatogenic cycle. According to this hypothesis all cells of one developmental stage within a given cell association are interconnected by intercellular bridges, thus forming a syncytium which contains each complete layer of a cell association. This explains the synchronous development of the cell layers. The coordination of the development of different layers of one cell association is effected by Sertoli cells. To achieve this organization of the spermatogenic cycle the entire cell population of one cell association has to be derived from one common embryonic stem cell. The evidence for this hypothesis is discussed.

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Zusammenfassung Untersuchungen der Ultrastruktur der Spermatogenese der Säuger haben intercelluläre Brücken in allen Zellgenerationen des Keimepithels ergeben. Desmosomen verbinden die Sertolizellen untereinander (Sertolizelle — Sertolizell-Verbindungen) und mit den benachbarten Zellen des Keimepithels. Um die verschiedenen Formen von Zellverbindungen in allen Entwicklungsstadien der Spermatogenese nachzuweisen, mußten die unterschiedlichen Zellgenerationen bestimmt werden. Dies wurde erreicht durch Beachtung der Morphologie der Zellkerne und durch die Zuordnung der Zellen zu den Zellassoziationen, in welchen sie beobachtet wurden.Diese Beobachtungen führten uns zu einer Hypothese, durch die die lokale Steuerung der Spermatogenese erklärt wird. Nach dieser Hypothese sind alle Zellen eines Entwicklungsstadiums innerhalb einer Zellassoziation durch intercelluläre Brücken verbunden. Hierdurch wird ein Syncytium gebildet, welches jeweils gesamte Zellschichten einer Zellassoziation umfaßt. Auf diese Weise wird die synchrone Entwicklung innerhalb der Zellschichten erklärt. Die Koordination der Entwicklung von verschiedenen Zellschichten einer Zellassoziation wird durch Sertolizellen bewirkt. Um diese Organisation des Spermatogenesecyclus zu erreichen, muß die Zellpopulation einer Zellassoziation von einer gemeinsamen embryonalen Stammzelle abstammen. Die Evidenz für diese Hypothese wird diskutiert.

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With support of the Deutsche Forschungsgemeinschaft.

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This paper is dedicated to Professor H. Grüneberg, F.R.S. on his retirement from the Chair of Animal Genetics at University College, London.     

Molecular mechanisms of the chromosome condensation and decondensation cycle in mammalian cells

The chromosomes undergo a condensation-decondensation cycle within the life cycle of mammalian cells. Chromosome condensation is a complex and critical event that is necessary for the equal distribution of genetic material between the two daughter cells. Although chromosome condensation-decondensation and segregation is mechanistically complex, it proceeds with high fidelity during the eukaryotic cell division cycle. Cell fusion studies have indicated the presence of chromosome condensation factors in mammalian cells during mitosis. If extracts from mitotic cells are injected into immature oocytes of Xenopus laevis, they induce meiotic maturation (i.e. germinal vesicle breakdown and chromosome condensation) within 2–3 hours. Recently, we showed that the maturation-promoting activity of the mitotic cell extracts is inactivated by certain protein factors present in cells during the G₁ period. The activity of the G₁ factors coincides with the process of chromosome decondensation that begins at telophase and continues throughout the G₁ period. These studies have revealed that the mitotic factors and the G₁ factors play a pivotal role in the regulation of condensation and decondensation of chromosomes. Furthermore, our studies strongly suggest that nonhistone protein phosphorylation and dephosphorylation may mediate chromosome condensation and decondensation, respectively.