Downloaded from http://cshperspectives.cshlp.org/ on September 30, 2021 - Published by Cold Spring Harbor Laboratory Press The Nucleus Introduced Thoru Pederson Program in Cell and Developmental Dynamics, Department of Biochemistry and Molecular Pharmacology, University of Massachusetts Medical School, Worcester, Massachusetts 01605 Correspondence: [email protected] Now is an opportune moment to address the confluence of cell biological form and function that is the nucleus. Its arrival is especially timely because the recognition that the nucleus is extremely dynamic has now been solidly established as a paradigm shift over the past two decades, and also because we now see on the horizon numerous ways in which organization itself, including gene location and possibly self-organizing bodies, underlies nuclear functions. “We have entered the cell, the Mansion of our microscopy, Antony van Leeuwenhoeck, did birth, and started the inventory of our acquired so with amphibian and avian erythrocytes in wealth.” 1710 and that in 1781 Felice Fontana did so as —Albert Claude well in eel skin cells. More definitive accounts followed by Franz Bauer, who in 1802 sketched hen I first read that morsel from Albert orchid cells and pointed out the nucleus (Bauer WClaude’s 1974 Nobel Prize lecture it 1830–1838), as well as by Jan Purkyneˇ, who seemed Solomonic wisdom, as it indeed was. described it as the vesicula germanitiva in Though he was referring to cell biology chicken oocytes (Purkyneˇ 1825), and Robert en toto, the study of the nucleus was then at a Brown who observed it in a variety of plant cells tipping point and new advances were just at (Brown 1829–1832), earning additional fame hand. Since then, the nucleus field has literally for coining the term “nucleus” (for excellent nucleated and we are now at a position to accounts of these early descriptions of the both admire the recent past and register excite- nucleus see Gall 1996; Harris 1999). Of course, ment about the present and where the nucleus these early observations did not ascribe particu- field may be headed. lar significance to this structure, the given name simply conveying its central location. Later, the nucleus was increasingly observed and became, THE NUCLEUS DISCOVERED with some prescience, a key tenet of the cell We cannot know who first saw the nucleus theory. The nucleus remained a rather lonely but we do know that the father of optical item in the eukaryotic cell’s parts list for many Editors: David L. Spector and Tom Misteli Additional Perspectives on The Nucleus available at www.cshperspectives.org Copyright # 2011 Cold Spring Harbor Laboratory Press; all rights reserved; doi: 10.1101/cshperspect.a000521 Cite this article as Cold Spring Harb Perspect Biol 2011;3:a000521 1 Downloaded from http://cshperspectives.cshlp.org/ on September 30, 2021 - Published by Cold Spring Harbor Laboratory Press T. Pederson decades, until the discoveries of discrete cyto- reticulum. The frequently observed intimacy of plasmic entities, e.g., mitochondria, the Golgi the nuclear envelope with the endoplasmic retic- apparatus etc. (reviewed in Wilson 1925). ulum has been often under-appreciated, particu- larly as it bears on the isolation of nuclei and issues of resulting purity. There is also growing THE NUCLEUS INHERITED interest in how nuclear membrane proteins We do not know how and when the genome of may be integrators of nuclear and cytoplasmic an ancestral cell first became encased in a prim- organization and dynamics (e.g., King et al. itive nucleus. We have no evidence that cells 2008; Roux et al. 2009; Starr 2009). living in the RNA world ever had a membrane A seminal finding was that the nuclear enve- (or any other structure) around the genome, lope contains pores (reviewed by Gall 1964; i.e., that they ever became nucleate. Once a ribo- 1967), which have now been defined in consid- zyme RNA replicase arose, anything would have erable compositional and structural detail (e.g., been possible including the emergence of ribo- Alber et al. 2007; Fernandez-Martinez and Rout zymes with lipid biosynthetic activities. 2009). A somewhat less familiar but equally Enthalpy-favored or free energy-driven important area of investigation has revealed events could then have led to stabilizing selec- that the nuclear envelope harbors a signal tion of RNA-lipid affinities and on from there. transduction system of its own, featuring play- A cottage industry of experiments on the inter- ers in common with the plasma membrane, actions of lipids with RNA has emerged in the for example the lipid-linked inositol trisphos- chemical biology field in the past decade but phate system (Martelli et al. 1991; for reviews the significance of these studies to prebiotic sys- see Divecha et al. 1993; Cocco et al. 2009; Barton tems and the earliest cells remains speculative. et al. 2010). As for the advent of the DNA world, and of eukaryotes, a major concept is that a proka- THE NUCLEUS DIVERSIFIED ryote organism was invaded by another, non- However the nucleus arose, it went on to display nucleated cell, setting up an endosymbiotic a variety of organizations. These range from the relationship, with the entering organism’s outer highly condensed nuclei of mature erythrocytes membrane seeding what would become the in nonmammalian vertebrates to the bimorphic nuclear envelope. The major proponent of this nuclei in almost all ciliates. In the latter organ- plausible idea has also suggested that this hypo- isms a micronucleus perpetuates the genome thetical invader also brought in a centriole, the whereas a macronucleus contains DNA frag- forerunner of what we know as the centriole/ ments that represent only a fraction of the basal body in extant eukaryotes (Margulis organism’s genome complexity and which et al. 2000). We can not play the videotape of encode the RNAs and proteins needed for veg- life on Earth backwards and although we can etative life. It was a particular feature of this reconstruct some things with a degree of empir- genomic strategy, namely the macronuclear ical confidence, albeit amidst debate (reviewed amplification of the ribosomal RNA genes by Misteli 2001a; Poole and Penny 2001; Rotte (Gall 1974), that led to the discovery of the and Martin 2001), or speculation (e.g., Lake telomere DNA sequence (Blackburn and Gall 2009), when it comes to how the nucleus 1978). It was also in these ciliates that self- arrived, we just do not know. splicing RNA was discovered and in which the era of chromatin epigenetic marks was launched THE NUCLEUS ENVELOPED (reviewed in Pederson 2010). Notwithstanding the uncertainty of its evo- THE NUCLEUS VIEWED lutionary origin, the nucleus is bounded by a double membrane, the nuclear envelope, which Beyond early observations made by bright field inmanycellsiscontiguouswiththeendoplasmic microscopy, the staining method developed by 2 Cite this article as Cold Spring Harb Perspect Biol 2011;3:a000521 Downloaded from http://cshperspectives.cshlp.org/ on September 30, 2021 - Published by Cold Spring Harbor Laboratory Press The Nucleus, Introduced Robert Feulgen, which attaches a dye to acid- THE NUCLEUS ISOLATED depurinated DNA, was a major tool in advanc- ing the DNA ¼ gene theory, based on studies of Using pus-soaked bandages from a local hos- the DNA content of haploid versus diploid cells pital, Friedrich Miescher discovered DNA in by a graduate student, Hewson Swift, in the the late 1860s. As described in a richly detailed laboratory of Arthur Pollister at Columbia historical account (Portugal and Cohen 1977), University, and concurrent ones by Hans Ris Miescher wrote a manuscript and submitted it in the laboratory of Alfred Mirsky at the to a top journal but had to sit by and wait while Rockefeller Institute (reviewed by Pederson the editor (and his former mentor), Felix 2005). Although biochemical measurements Hoppe-Seyler, checked the findings in his own of the DNA contents of germ versus somatic lab, resulting in the publication of two con- cells had revealed a twofold difference, these current papers (Miescher 1871; Hoppe-Seyler findings mostly remained in the biochemical 1871). Over the next 90 years, efforts to isolate community and did not have as much impact nuclei did not go very far. In the 1960s Alfred as might have been expected. It was the Feulgen Dounce at the University of Rochester, Van cytophotometry results that helped catalyze the Potter and Conrad Elvehjem at the University idea that DNA is genes. This was, to borrow part of Wisconsin, and Philip Siekevitz and George of Winston Churchill’s famous phrase—“the Palade at the Rockefeller Institute pioneered end of the beginning” (Avery et al. 1944). the isolation of nuclei from animal tissue. (The Meanwhile, phase contrast microscopy had Rochester and Wisconsin investigators had beautifully revealed the interphase nucleus and the homogenizers they developed named for mitotic chromosomes, the latter not “nuclear” them.) Important advances in isolating nuclei in the strictest sense. Electron microscopy led from plant tissue were made at approximately to the visualization of the double nuclear mem- the same time by James Bonner’s group at brane and nuclear pores (Gall 1964; 1967), the Caltech. Later, groups at Baylor College of Med- tripartite structure of the nucleolus (Bernhard icine (Harris Busch), Rockefeller University et al. 1952), the nuclear lamina (Fawcett 1966), (Alfred Mirsky) and Albert Einstein College of and subsequently the observation of chromatin Medicine (Sheldon Penman) published refined n-bodies (Olins and Olins 1974), later re-named methods. As is the case for most cell fractiona- nucleosomes (Oudet et al. 1975). tion methods, none of these proved to be perfect An intriguing nuclear structure first ob- but they were major advances nonetheless. served by the Spanish neuroanatomist Santiago The fact that the endoplasmic reticulum Ramon y Cajal (Cajal 1903, 1910) underwent a and the nuclear envelope are contiguous in renaissance of interest when one of its protein many cells is but one example of this challenge, components was identified by Eng Tan and and the tendency of the cytoplasmic intermedi- colleagues (Andrade et al.