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And Cytogenesis of the Vertebrate CNS Int..J.De\'. BioI. 38: 175-183(1994) 175 Specinl Review Early events in the histo- and cytogenesis of the vertebrate CNS JUNNOSUKE NAKAI" and SETSUYA FUJITA' 'Hamamatsu Photonics, Hamamatsu and 2Department of Pathology, Kyoto Prefectural University of Medicine, Kyoto, Japan CONTENTS Prelude to neurogenesis 176 Nature of matrix cells, pluripotent precursor cells in the CNS.. 176 GFAP and matrix cells ............................................ 177 Determination of cell differentiation and its possible genetic mechanisms 177 Major differentiation of matrix cells 178 Major differentiation and formation of neuronal and neuroglial cells 180 Irreversible gene inactivation and neural plasticity 180 Mechanism of pathfinding and the principle of multiple assurance in neurogenesis 181 Summary and key words ................................................... ............................................... 182 References. ." ...... 182 -Address for reprints: Hamamatsu Photonics, 4-26-25, Sanarudai, Hamamatsu 432, Japan. 0214-6282/94/$03.00 e URC Pr~" Pr;nl~d in Spain -- 176 .I. Nakai alld S. Flljila Prelude to neurogenesis number as the blastula proceeded to neurula. The obliteration of initiation sites of DNA replication seems to be accompanied by the Neural induction has been regarded as the earliest event in absolute incapability of RNA synthesis on that replicon, while DNA neurogenesis in all the vertebrate embryo. Before neural compe- appears to be replicated as a continuation from the neighboring tence appears, however, continuous cellular and chromosomal replicons though taking longer to complete the replication. At the processes proceed in the cleaving embryo culminating in neural light microscopic level, the synchrony of the cell division is lost induction. In aplacental animals, such as amphibia, reptiles and rapidly during this period as a result of progressive elongation of the birds, the first 10 or so cleavage divisions are mostly synchronous cell cycles. and the cell cycle is very short, virtually lacking G1 and G2 phases. Yamazaki- Yamamoto el al. (1980, 1984) have studied changes in Nature of matrix cells, pluripotent precursor cells in the C banding patterns and morphology of chromosomes in Cynops CNS pyrrhogasler embryos and found that during this phase (from fertilization to the beginning of blastula stage), the metaphase The analysis of cell proliferation and differentiation of stem celis chromosomes remain unchanged in morphology and C banding in developing vertebrate embryos revealed that there are highly pattern. They found, however, that remarkable shortening, almost regulated patterns in the genesis of neuronal and glial populations halving in length, occurred from blastula to gastrula stage accom- in the vertebrate CNS. At the beginning, there is a stage in which panied by a prominent decrease in chromosome volume, as the the neural tube is composed solely of pluripotent progenitor cells, chromosomal width was kept constant. During this period, many C matrix cells (matrix means "progenitor", Fujita, 1962). At this stage bands fused with the neighboring ones and reduced in number as (called stage I), matrix cells proliferate only to multiply themselves the blastula proceeded to neurula The neural competence ap- (Fujita, 1963). They perform the elevator movement synchronous peared in blastula stage, immediately after the shortening of the to their mitotic cycle (Fig. 2A). chromosomes began. It is weli known that atthe same time, dermal The matrix cells compose pseudostratified columnar epithelium differentiation in the embryo is determined and morphogenetic of the neural tube and adhere, during interphase, to each other with movements and migration of individual dermal cells begin to take N-cadherin (Takeichi, 1990). When they enter into mitosis, the place. adhesion ceases and the cell bodies round up. Throughout mitosis, These chromosomal changes that seem to lead to neural the junctional complex in the apical process remains unchanged so induction and neurogenesis are characterized by the remarkable that the cell body is inevitably pulled towards the ventricular elongation of S-phase in the cell cycle, from 3 h in morula stage to surface. Fujita (1990) examined distribution of F-actin that lines the 38 h or more in neurula stage (Yamazaki-Yamamoto et a/., 1980). cell membrane of the dividing matrix cell by confocal microscopy The time spent for DNA replication is prolonged (Fig. 1). The same and concluded that F-actin is depolymerized during mitosis, re- phenomenon continues in the neural tube. Autoradiographic stud- leased from linker molecules binding cadherin and F-actin and, as ies have revealed remarkable increases in DNA-synthetic times a result, dissociation of the cadherin-mediated adhesion takes during neural tube development as reported by Fujita (1962,1986), place during mitosis (Fig. 36). Fujita (1990) regards this cyclic Hoshino et al. (1973) and others. Accordingto Hyodo and Flickinger modulation of N-cadherin adhesion during mitosis as the mecha- (1973), the velocity of DNA replication within each replicon, as nism of the elevator movement. studied in frog embryos, is almost constant, being 6 ~lm/h. The After several mitoses during stage I, matrix cells begin to length of each replicon, however, increases as the development of differentiate neuroblast. This stage of neuron production is called frog Rana lasca proceeds, being estimated at 11, 27 and 29 ~m, stage II of cytogenesis (Fujita, 1964). There appears to exist a rigid in gastrula, neurula and tail bud stage, respectively. Obviously, and close correlation between the time and place of birth and the initiation sites of DNA replication in some replicons are progres- type of neuron differentiation determined at the birth of each sively obliterated or, in other words, many replicons fuse with the neuroblast. neighboring ones as development proceeds. The same phenom- Once the neuroblast is differentiated from matrix celis, most, if enon may be reflected in the observation mentioned above that not all, features of the future neuron are irreversibly fixed and many C bands fused with the neighboring ones and reduced in cannot be altered by subsequent dislocation or environmental changes. In the CNS, modification of neuron types can only occur at an early stage of matrix cells if the environment is changed. This ,lbhrl'1,jaliOl/\ /1.\1'11in Ihi.'i ImIH'r: C:'\S.n:!llra] ncn'Olis system; GFAP, G1ia fibril1ary acir\ic pnJf('in; Sl)S I'.\(;E. s()dium dode('y] s\l1fau' V1]~acl"ylamide has been confirmed (Cavines, 1982) in the mutant mice in which gel c]cctrop]!()rcsis. location of the cortical neurons is drastically disordered but type of Early erents in nellrogenesis 177 nu.tlerof,ells , ,. ,. , ,. I " " " " I " " " " " nUilberofdirisions , , , . , , , 00 .. " " " " .iloti,sv!lclroll, synclJronous be,CQiniI.Syn,hronous uyntllronous ;' ,e!J",!e s...." s....s"'s , , . elonil.tionofSphue Fig. 1. Cell division, chromosomal clJr~s(:illles ~IUVlietype '.blulu I. t p.stru!l.ty changes and appearance of neural competence in early development of I;coPeteoce..r none Cynops pyrrhogaster (Yamazaki- neun.!induction Yamamoto et al.. 1980). They desig- nated short and condensed chromo- dnelo~ntl.lstar- cleul.2e DJrul. bllstul. 2Istrul. somes at gastrula stage as 'gastrula , , time3.fter ;5 ~.~ (hr) type chromosomes'. lerti!izatioo 10 N " '" " neuron differentiation unchanged. Transplantation into heterotopic cord (Fujita et al.. 1986). The occurrence of the GFAP-encoded sites (Nakamura et al., 1986) or explantation in vitro have also mRNA is studied using this cDNA probe. The signal of GFAP- failed to change the original type of differentiation of neurons in the encoded mRNA is found only postnataliy, and notrace 01the signal CNS. It is likely that determination at the neuroblast differentiation is detected in RNA fraction offetal rat cerebrum (embryonic day 16, takes place at an early G1 of the matrix celi (Fujita. 1963). 22). A similar observation was reported by Lewis and Cowan When ali the neurons are produced. stage II ends and the stage (1985) with mouse GFAP-mRNA. They found weak positive signal 01neuroglia production begins (Fujita, 1965b). Matrix celis are now first at postnatal day 2, which increases until day 9 followed by a restricted to producing only non-neuronal cells and change into slight decrease to the adult. In their experiment, embryonic mouse ependymoglioblasts, which are soon differentiated into ependymal brains did not show any positive signal of GFAP-encoded mRNA. celis and glioblasts. This is stage III at cytogenesis. The glioblast In chicken brains, Capetanaki et al. (1984) also obtained the same (Fujita, 1965b) is a common progenitor of neuroglial cells at the result, i.e., that up to day 10 at incubalion (the end of stage II) no CNS, and first differentiate astrocytes, then oligodendroglia and trace of GFAP mRNA was detectable by Northern blotting but that finally metamorphose into the microglia (Fujita et al., 1981). Based strongly positive signal appeared in the spinal cord 2 weeks after on the monophyletic theory described above, cell differentiation in hatching. the developing vertebrate CNS is explained with a simple scheme The result reveals that the occurrence of the GFAP-encoded shown in Fig. 3A. mRNA parallels the appearance of the GFAP molecules in the developing CNS as described previously (Fujita, 1986), and that, GFAP and matrix cells in rat as well as chicken and mouse brains, transcription of GFAP- encoded gene first
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