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Reconstructions of Centriole Formation and Ciliogenesis in Mammalian Lungs

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Reconstructions of Centriole Formation and Ciliogenesis in Mammalian Lungs J. Cell Sci. 3, 207-230 (1968) 207 Printed in Great Britain RECONSTRUCTIONS OF CENTRIOLE FORMATION AND CILIOGENESIS IN MAMMALIAN LUNGS S. P. SOROKIN Department of Anatomy, Harvard Medical School, Boston, Massachusetts 02115, U.S.A. SUMMARY This study presents reconstructions of the processes of centriolar formation and ciliogenesis based on evidence found in electron micrographs of tissues and organ cultures obtained chiefly from the lungs of foetal rats. A few observations on living cultures supplement the major findings. In this material, centrioles are generated by two pathways. Those centrioles that are destined to participate in forming the achromatic figure, or to sprout transitory, rudimentary (primary) cilia, arise directly off the walls of pre-existing centrioles. In pulmonary cells of all types this direct pathway operates during interphase. The daughter centrioles are first recognizable as annular structures (procentrioles) which lengthen into cylinders through acropetal deposition of osmiophilic material in the procentriolar walls. Triplet fibres develop in these walls from singlet and doublet fibres that first appear near the procentriolar bases and thereafter extend apically. When little more than half grown, the daughter centrioles are released into the cyto- plasm, where they complete their maturation. A parent centriole usually produces one daughter at a time. Exceptionally, up to 8 have been observed to develop simultaneously about 1 parent centriole. Primary cilia arise from directly produced centrioles in differentiating pulmonary cells of all types throughout the foetal period. In the bronchial epithelium they appear before the time when the ciliated border is generated. Fairly late in foetal life, centrioles destined to become kinetosomes in ciliated cells of the epithelium become assembled from masses of fibrogranular material located in the apical cytoplasm. Formation of these centrioles may be under the remote influence of the diplosomal centrioles. More certainly, the precursor material accumulates in close proximity to Golgi elements. Within the fibrogranular areas, osmiophilic granules (400-800 A) increase in size and eventually become consolidated into dense spheroidal bodies (deuterosomes), which organize the growth of procentrioles around them. When mature, the newly formed centrioles become aligned in rows beneath the apical plasma membrane. There each centriole produces satellites from its sides, a root from its base, and a cilium from its apex. Early stages in the formation of both primary cilia and those of the ciliated border are similar. In developing cilia of the ciliated border, however, the outer ciliary fibres rapidly reach the tips of the elongating shafts, and a central pair of fibres is formed (9 + 2 arrangement). In primary cilia, development of the fibres seems to lag behind the elongation of the shafts, and only the outer ciliary fibres appear (9 + 0 arrangement). The strengths and weaknesses of the proposed reconstructions of centriolar formation and ciliogenesis are discussed, and the occurrence in other living forms of similar pathways for centriolar formation is noted. Further discussion leads to an interpretation of the centriole as a semi-autonomous organelle whose replicative capacity is separable from the characteristic triplet fibre structure of its wall. 208 S. P. Sorokin INTRODUCTION During the development of the lung, two distinct types of cilia are formed: rudi- mentary cilia and those of the ciliated border. The rudimentary cilium is the first to appear. It is produced as a solitary appendage by virtually all of the cells present, including those that later develop a ciliated border. The cilium grows out directly from one centriole of the pair that participates in organizing the achromatic figure, and it seems to have only a transitory existence. In being a direct derivative of the achro- matic centrioles and the first cilium to emerge from the cells, the rudimentary cilium may be termed 'primary' and the process of its formation 'primary ciliogenesis'. Beginning at a later stage of pulmonary development, a second and more familiar kind of cilium is produced by those epithelial cells that are destined to possess a ciliated border. Numerous basal bodies (kinetosomes) at first become visible in the cytoplasm of these cells. Then a long, motile cilium grows out from each basal body. This paper reconstructs from electron micrographs the cytological events that are connected with the formation of the basal bodies and the generation of both types of cilia. One of the most interesting problems related to the genesis of a ciliated epithelial border concerns the formation of the basal bodies, which in most higher animals are morphologically identical to the centrioles. Indeed, it has long been widely accepted that centrioles divide to form the basal bodies (Henneguy, 1898; von Lenhossek, 1898; Lwoff, 1950). None the less, some investigators have shown that centrioles (Faure- Fremiet, Rouiller & Gauchery, 1956; Bernhard & de Harven, i960) or basal bodies (Gall, 1961) may arise from a position off the wall of a parent centriole, where they almost certainly are not formed by division of the pre-existing organelle. Others have suspected, in the case of ciliated cells, that the basal bodies are formed de novo in the cytoplasm (Randall et al. 1963; Stockinger & Cirelli, 1965). In this paper it will be shown that centrioles or basal bodies can be produced either directly from a pre- existing centriole or indirectly through a range of precursors that do not resemble centrioles. Furthermore, the results permit one to see that the reproductive capacity of a typical centriole is separable from its characteristic triplet fibre structure. Where this study is concerned with centrioles, however, it is limited to a consideration of the 9-membered cylindrical organelle that performs the centriolar functions in most animal cells. It does not encompass a view of other more unusual centrioles that occur in certain flagellates (Cleveland, 1957), in testicular cells of fungus gnats (Phillips, 1966), and in other subjects of the animal kingdom. The reconstructions presented in this paper are based on study of an extensive series of electron micrographs. There is some reason to remark that the reconstruction of a biological process from a series of stages can express a hypothesis, but that it does not establish its truth. In the cases of centriolar formation and ciliogenesis, however, no more than a superficial understanding of these processes so far has been achieved. Some merit may therefore be found in the reconstructions offered if they are helpful in establishing the conceptual framework that so often precedes the design of subtle and telling experiments. Centriole formation and ciliogenesis 209 MATERIALS AND METHODS The developing lungs of foetal rats were the principal materials used for study. They were examined by light and electron microscopy both as they matured in utero and in organ culture (Sorokin, 1961). The normally developing lungs ranged in age from 14 to 21 days of gestation if the morning when spermatozoa were found in the vagina of the mother rat was designated day 1. Organ cultures were explanted on all days between the 14th and 19th and were cultured for varying periods up to 10 days. In general, the ciliated border first appeared in the epithelium of trachea and primary bronchi during the 20th day of gestation or at a corresponding age in vitro, as judged both by examination of sections and by study of living cultures. Consequently attention was focused on lungs that fell in the 19- to 22-day range. In contrast to the preceding, primary cilia could be observed to undergo formation during the entire period surveyed. In addition to the material from rats, tissues from newly hatched chicks were examined for centrioles and primary cilia. Specimens for microscopy were fixed in barbiturate- or phosphate-buffered osmium tetroxide, as well as in glutaraldehyde plus osmium tetroxide or formaldehyde- glutaraldehyde plus osmium tetroxide (Karnovsky, 1965), and all were embedded in Epon. One-micron sections taken for light microscopy were stained with toluidine blue, while thin sections cut with glass knives for electron microscopy were stained sometimes with lead plumbite or lead citrate and sometimes with uranyl acetate. The grids were examined in RCA microscopes EMU 3 E, 3 F, or 3 G. OBSERVATIONS Primary cilia The primary cilia of mammalian lungs resemble closely the rudimentary, or abortive, cilia that are known to occur in a wide variety of cells present in other organs (Zimmer- mann, 1898; Barnes, 1961; Latta, Maunsbach & Madden, 1961; Sorokin, 1962; Grillo & Palay, 1963; Dahl, 1963; Adams & Hertig, 1964; Schuster, 1964; Motta, 1965; Deane & Wurzelmann, 1965; Wheatley, 1967; Breton-Gorius & Stralin, 1967). In the lung such cilia are produced by virtually all of the cell types present during formation of the lung and its glands. During normal development the cilia are in peak production while cells are actively undergoing differentiation. That is, while most of the cells are sufficiently differentiated to be recognizable as to type—fibroblast, chondrocyte, myocyte, epithelial cell (Fig. 18), or mesothelial cell (Fig. 19)—they retain certain characteristics of immaturity, such as an open chromatin pattern in the nucleus, and the presence of many free ribosomes, of glycogen, or of triglyceride (Sorokin, Padykula & Herman, 1959) in the cytoplasm. Epithelial cells in developing bronchi produce primary cilia some days before they begin to produce a ciliated border, and a single cilium may protrude from an immature goblet cell (Fig. 13). Primary cilia occur occasionally in cells of adult lungs, but they occur far more frequently in developing tissues, where they easily are spotted by electron microscopy in scanning grids of thin sections. Owing to their scarcity in adult tissues, these cilia are considered to have 210 S. P. Sorokin only a transitory existence. The cells of adult lungs that possess such cilia are interpre- ted to be undergoing maturation from an indifferent state, after being released to differentiate into replacements for worn elements of the lung.
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