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(The FASEB Journal. 2000;14:828-834.)
© 2000 FASEB

Heterogeneous ectopic RNP-derived structures (HERDS) are markers of transcriptional arrest

MARCO BIGGIOGERA1 and CARLO PELLICCIARI

Dipartimento di Biologia Animale, Laboratorio Biologia Cellulare, and Centro di Studio per l’Istochimica del CNR, University of Pavia, 27100 Pavia, Italy

1Correspondence: Dipartimento di Biologia Animale, Laboratorio Biologia Cellulare, Piazza Botta 10, 27100 Pavia, Italy. E-mail: marcobig{at}unipv.it


   ABSTRACT
TOP
 ABSTRACT
INTRODUCTION
 Different conditions, similar...
 HERDS are storage sites...
 RNPs from HERDS may...
 HERDS are morphological markers...
 REFERENCES
 
We have reviewed the reports in the literature concerning the segregation and clustering of ribonucleoprotein (RNP) -containing nuclear structures in either physiological or experimentally induced conditions (i.e., spermiogenesis and erythropoiesis in mammals, early embryonic development, hibernation, spontaneous and drug-induced apoptosis, treatment with different drugs). Irrespective of the biological system or the experimental conditions, heterogeneous ectopic RNP-derived structures (HERDS) are always found. We hypothesize that the common event at the basis of this phenomenon might be the block in transcription; this is also consistent with our own and others’ results on cultured cells after actinomycin D treatment. HERDS may therefore be considered as the morphological sign of transcriptional arrest. Based on the evidence that the restructuring/relocation of RNPs may be reversible, we also hypothesize that HERDS may serve as storage sites from which RNPs may be eventually retrieved, as soon as transcription restarts. Under acute stress conditions or during apoptotic cell death, the same reorganization of RNP-containing structures would be an adaptively suitable mechanism to induce an irreversible arrest in RNA processing, thus effectively blocking protein synthesis.—Biggiogera, M., Pellicciari, C. Heterogeneous ectopic RNP-derived structures (HERDS) are markers of transcriptional arrest.


Key Words: ribonucleoproteins • transcriptional arrest • immunocytochemistry • heterogeneous ectopic RNP-derived structures


   INTRODUCTION
TOP
 ABSTRACT
 INTRODUCTION
Different conditions, similar...
 HERDS are storage sites...
 RNPs from HERDS may...
 HERDS are morphological markers...
 REFERENCES
 
NUCLEAR RIBONUCLEOPROTEINS (RNPS) are associated with and are actually part of the transcription and splicing machinery. In eukaryotic cells, RNPs are always organized as morphologically recognizable structures known as perichromatin fibrils (PF), perichromatin granules (PG), and interchromatin granules (IG). These structures have been described at the electron microscope (see ref 1 for a review) and characterized in situ, especially by means of specific antibodies; this approach allowed to understand the different roles played by all these constituents in the transcriptional process (2 3 4) .

In particular, PF have been recognized as the morphological equivalent of hnRNA transcription and cotranscriptional splicing; in fact, they were shown to contain newly synthesized RNA (5) , hnRNPs, snRNPs, as well as the non-snurp SC35 splicing factor (6) . IG represent a storage site for snRNP and non-snRNP splicing factors (1) and a possible site for the assembly of spliceosomes (7) . Finally, PG are involved in the storage and the nucleus-to-cytoplasm transport of mRNA (1) . Moreover, the role played by another nuclear component, the coiled body (CB), seems to be related to a transport or withdrawal of splicing factors and/or other proteins to and/or from both pre-mRNA and pre-rRNA transcription sites (see refs 8 , 9 ).

All these components (with the exception of the CB) have specific intranuclear locations: at the periphery of condensed chromatin (PF and PG) and in the so-called interchromatin space (IG). The correct intranuclear location of these RNP-containing particles is a necessary prerequisite for the maturation of nuclear RNAs (for a review, see ref 10 ).

We have recently found that during apoptosis, in parallel with chromatin condensation, these structures first segregate in the nuclear areas where loose chromatin is located and then coalesce into heterogeneous clusters we have called HERDS (heterogeneous ectopic ribonucleoprotein-derived structures; ref 11 ).

In the present paper, we shall use the acronim HERDS to indicate all those RNP-containing heterogeneous structures (at least two, resembling well-defined nuclear components) that have been observed outside their normal nuclear locations, irrespective of the different terms possibly used originally in the literature.

During apoptosis, HERDS pass into the cytoplasm and are finally extruded from the cell within membrane-bound cellular debris (12 , 13) it must be noted that some RNA is still present in these structures even when they are extruded from the cell (11) .

This clustering of RNPs during apoptosis recalls the similar phenomenon taking place in the mammalian spermatid nucleus at the so-called elongation phase (14 , 15) , when one or more clusters formed by heterogeneous fibrogranular particles are found in the nucleus. These clusters have been shown to be labeled by anti-Sm antibodies and, to a lesser extent, by anti-hnRNP probes (15) .

The presence of non-nucleolar ribonucleoproteins such as snRNPs and SC-35 has been demonstrated in nucleolus-like bodies in pig (17) and rat (18) . A similar situation occurs in nucleolus precursor bodies (NPB) of early embryos from several mammalian species (16 , 17 , 19) . With the onset of transcriptional reactivation, these NPB will give rise to functional nucleoli, probably after releasing their snRNP and hnRNP proteins into the nucleoplasm.

Several other examples of restructuring and relocation of nuclear RNP containing structures may be found in the literature; we therefore decided to reconsider all these different conditions and a few original data.

Besides spermiogenesis, early embryonic development, and spontaneous thymocyte apoptosis, we reviewed 1) adult erythrocyte maturation in mammals (20) ; 2) drug or stress induced apoptosis (personal observations); 3) hibernation; 4) lasiocarpine, aflatoxin, and nitroquinoline treatment (21 , 22) . In addition, we paid attention to the so-called passenger proteins during mitosis (23) . In all these situations, RNPs give rise to heterogeneous fibrogranular particles that strongly resemble HERDS, although their final fate may vary, as we describe below.


   Different conditions, similar phenomenon
TOP
 ABSTRACT
 INTRODUCTION
 Different conditions, similar...
HERDS are storage sites...
 RNPs from HERDS may...
 HERDS are morphological markers...
 REFERENCES
 
To follow the redistribution/relocation of RNP-containing structures, we have considered a group of proteins that are, either directly or indirectly, involved in the pre-mRNA or pre-rRNA transcription and maturation. We have briefly summarized these findings in Table 1 . It is clear that all of them can relocalize either in heterogeneous clusters or as chromosomal passengers. This mobility is not surprising when considering that IG, for instance, can play the role of both storage and recruiting site for splicing factors (see ref 24 for a new hypothesis).


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  		Table 1. Relocation of some nuclear or nucleolar proteins after transciptional arresta

Spermiogenesis
As already pointed out (14) , clustering of RNP occurs in the elongation spermatid nucleus (Fig. 1a ). Some of these RNP have been characterized as snRNPs (Sm antigen) and hnRNP (15) . As soon as chromatin begin to condense, they are no longer visible. The fate of these cluster so far is not clear: a part could be degraded and the rest might be masked in the condensing nucleus of the late spermatid (for instance, within the ‘flowers’ that sometimes are visible in the vacuoles of chromatin; refs 25 26 27 ). In addition, they do not contain any known nucleolar protein, being nevertheless silver stainable (25) .



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  		Figure 1. a) Mouse elongating spermatid (step 10). Immunolabeling for anti-Sm. The heterogeneous cluster of RNPs is heavily labeled. Some of the structures forming this cluster are recognizable as IG. PG-like granules are present (arrows). Larger dense structures are also visible (arrowhead). b) Polychromatophilic erythroblast from rat bone marrow. Labeling for SC35 splicing factor. The condensed chromatin is bleached by EDTA staining and RNPs aggregates (arrows) are present in the interchromatin space. Inset: higher magnification of labeled HERDS. c) Mouse thymocyte undergoing spontaneous apoptosis. Typically, HERDS (in this case presumably formed by PF and IG) are labeled by the anti-Sm antibody. C: bleached chromatin. d) Mouse thymocyte undergoing apoptosis after etoposide treatment. HERDS are present in the cytoplasm. Note the nuclear fragments after karyorrhexis (arrows). e) Chromosomal passengers: the RNP layer (arrows) at the periphery of metaphase chromosomes in a Hep-2 (human larynx carcinoma) cell is clearly evident even in glutaraldehyde-osmium fixed preparations. f) Hepatocyte from Rana esculenta during hibernation (January). Two HERDS are present in the interchromatin space (arrows). Such HERDS can be found easily in hibernating animals and do not occur during the active period. Arrowheads point at the condensed chromatin areas that are typical of hibernation. a–d, f) Paraformaldehyde fixation, LR White embedding, and EDTA regressive staining. e): Glutaraldehyde fixation, osmium postfixation, LR White embedding, followed by uranyl-lead staining. Bars represent 0.2 µm.

Nucleolus precursor bodies
NPB and oocyte nucleolus-like bodies (17 18 19) can also be considered as a particular form of RNP segregation. It has been shown that they do not contain DNA (28) , but cytochemically detectable RNA (16) . Moreover they are labeled with antibodies recognizing hnRNPs, snRNPs (16) , SC-35 splicing factor, and fibrillarin (16 , 17 , 19) . However, different species show remarkable differences concerning the type of non-nucleolar RNPs detected within the NPB (29 , 30) . When nucleolar activity is resumed (at different blastomere stages, depending on the species), the dense mass constituting the NPB is fragmented, the new nucleolus is formed, and the reactivity to the above antibodies is lost.

Erythropoiesis in mammals
During the course of maturation of the erythroblast to erythrocyte, the nuclear activity is switched off and chromatin condensation occurs along with RNP segregation (20) . Nuclear RNPs, segregated in the interchromatin space left by the dense masses of already condensed chromatin, are still labeled by anti-Sm, anti-hnRNP as well as by anti-SC35 antibodies (Fig. 1b ). Finally, terminal differentiation occurs with the extrusion of the whole nucleus from the cell.

Apoptosis
RNP clustering (11 12 13) has been observed in both spontaneous (Fig. 1c ) and induced apoptosis (Fig. 1d ). Part of the RNP moiety is degraded (see ref 31 ) and another conspicuous part of the HERDS (including nucleolar remnants) is extruded from the cell via blebbing. In the latter case, some antigens are clearly recognizable by specific probes and hence can be of interest as one of the possible bases of autoimmune disease (11 12 13 , 31 , 32) .

Hibernation
During hibernation, several changes occur in the nuclear distribution of RNPs, and the formation of a number of different nuclear bodies has been recently described and characterized in the dormouse (refs 33 , 34 and references therein). These phenomena occur in different tissues (liver, adrenal gland etc.) whose transcription activity dramatically decreases in winter (Fig. 1f ). Most such nuclear bodies rapidly disappear at arousal, thus indicating a possible storage role for nuclear RNPs.

Drugs
It must be noted that different drugs show similar effects: lasiocarpine, aflatoxin, nitroquinoline, and others (21 , 35) all lead to the formation of RNP clusters (as seen after EDTA staining) in which IG are still recognizable (22) . Other treatments, nevertheless, provoke a similar phenomenon, and it is interesting to reconsider the EM micrographs from the 1960s and 1970s when all these treatments were performed. Lazarus and co-workers (35) came to the interesting conclusion that these ‘inclusions’ originate from the redistribution of an already synthesized material accumulated after the arrest of transcription.

As an addendum, we could also consider in this section the nuclear bodies formed after the use of antisense oligonucleotids (36) .

Interestingly enough, there is a common event in all these apparently different cell systems, i.e., the arrest or the absence of RNA transcription.

To test the hypothesis that a block in transcription may be at the basis of HERDS formation (see Fig. 2 ), we investigated the effects of actinomycin D (AMD) treatment of cells in culture.



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  		Figure 2. A scheme showing our view of RNP segregation and their fate in different biological systems. Spermiogenesis was tentatively placed among the examples of reversible HERDS formation because of the transitory inactivation of the male genome in which transcription may be reactivated on fertilization; in fact, there is no direct evidence for the recruitment of RNP proteins from HERDS of male origin, although Brito et al. (43) found their presence in the nuclei of fully mature rat spermatozoa.

When used at low concentration, AMD is considered to block preferentially RNA polymerase I, thus affecting nucleolar RNA synthesis, whereas high concentrations also perturb pre-mRNA synthesis in the nucleoplasm. After AMD treatment, it has been shown that besides nucleolar segregation, the formation of so-called nuclear inclusions occurs (22) . These inclusions were defined as being formed by RNA trapped in the nucleoplasm due to the drug effect and originated from the redistribution of an already synthesized material (35) . We have found that such inclusions contain both hnRNPs and snRNPs (unpublished observations).

It is therefore confirmed that also after AMD treatment, the arrest in transcription may be responsible for the origin of HERDS.


   HERDS are storage sites for RNPs
TOP
 ABSTRACT
 INTRODUCTION
 Different conditions, similar...
 HERDS are storage sites...
RNPs from HERDS may...
 HERDS are morphological markers...
 REFERENCES
 
RNP-containing structures (namely, IG and the CB) represent the nuclear sites for the storage of factors involved in RNA maturation (1) ; this is true particularly for IG, where snRNP and non-snRNP splicing factors may be transiently stored and the assembly of spliceosomes takes place (7 , 37) .

HERDS might represent storage sites for RNP-associated proteins whenever their intranuclear amount exceeds the association capability of newly transcribed and/or in-process RNAs.

If we take into account that RNP proteins have a relatively long half-life (38 , 39) and that RNP complexes are rather resistant to proteolytic cleavage, it is likely that HERDS in the absence of transcription may serve as a ready-to-use reservoir of proteins needed for RNA processing as soon as transcription is resumed.

A similar phenomenon takes place during mitosis, when many RNP proteins behave as passenger proteins and cluster at the chromosome periphery (Fig. 1e ). These proteins include fibrillarin, perichromin, Sm antigen, Ki-67 antigen, and several other proteins (40 , 41) , and form a layer of EDTA-positive material. This family of proteins has been named chromosomal passengers (23 , 40) . Among these proteins, it is important to underline the presence of factors involved in the synthesis of both pre-mRNA and pre-rRNA. RNA polymerases I and II are, for instance, present at this level (M. Biggiogera et al., unpublished results). This layer of protein is finally redistributed in the cell nucleus as soon as the mitotic phase ends and cell division takes place. When, for instance, fibrillarin is inhibited from moving at the end of mitosis by microinjected antibodies, the reassembly of nucleoli is altered (42) .


   RNPs from HERDS may have different final fates
TOP
 ABSTRACT
 INTRODUCTION
 Different conditions, similar...
 HERDS are storage sites...
 RNPs from HERDS may...
HERDS are morphological markers...
 REFERENCES
 
The results obtained on early embryos, where NPBs give rise to functional nucleoli, and those on elongating spermatids (and perhaps mature spermatozoa; ref 43 ) suggest that RNPs may only be transiently stored in HERDS, from which they may give rise to normally functioning IG, PF, and PG as soon as transcription is resumed.

Although we have at present no direct experimental evidence, it is likely that the protein components of those HERDS formed after stimuli blocking transcription may also move back to their normal nuclear structural location as soon as the exogenous stress ceases (at least in the presence of a limited damage).

On the contrary, whenever the cellular damage is massive (as it may occur during apoptosis or after an acute drug treatment) or in terminally differentiated cells such as mammalian erythrocytes, the formation of HERDS become irreversible. Under these conditions, however, HERDS may behave differently; they may be extruded from the nucleus (like during apoptosis) or be kept as nonfunctional complexes inside the nucleus (as in mammalian erythrocyte nuclei, at the very end of their cytodifferentiation). The integrity of the nuclear envelope (in particular, of the nuclear lamina) should be responsible for keeping HERDS in the nucleus (on the contrary, lamins are among the protein targets of caspases, during apoptosis; ref 44 ).


   HERDS are morphological markers of transcriptional arrest
TOP
 ABSTRACT
 INTRODUCTION
 Different conditions, similar...
 HERDS are storage sites...
 RNPs from HERDS may...
 HERDS are morphological markers...
REFERENCES
 
HERDS may form rapidly or as the consequence of slow processes. Actually, they are observed during apoptosis (which is a rapid process taking place in hours or even minutes) or during spermiogenesis, which is characterized by a long-lasting and constant decrease in the transcription rate.

In any case, the examples listed in this study strongly suggest that HERDS may be considered as morphological signs of altered RNA synthesis and/or pre-mRNA processing.

In the absence of a molecular mechanism accounting for the (sometimes reversible) restructuring and relocation of RNP-derived proteins, we may speculate on the functional meaning of this process. The examples of reversible HERDS formation (spermiogenesis, early blastomeres, cells from hybernating animals) makes it likely that this rearrangement may represent an effective means to accumulate and eventually preserve long-living proteins in a (potentially) functional state. Under acute stress conditions or during apoptotic cell death, the same reorganization of RNP-containing structures would be an adaptively suitable mechanism to arrest rapidly RNA processing, thus effectively blocking protein synthesis, whereas proteolytic cleavage by caspases and DNA degradation by endogeneous activated nucleases induce the structural and functional disruption of cell machineries.


   ACKNOWLEDGMENTS
 
The authors are indebted to Dr. Maria Grazia Bottone (Dipartimento di Biologia Animale, University of Pavia) for the immunofluorescence analysis of HERDS. The authors acknowledge Dr. Milvia Lotzniker (Laboratorio di Analisi Chimico-Cliniche, IRCCS San Matteo, Pavia) for the kind gift of the anti-Sm autoimmune serum. The experiments on hibernating frog were performed in collaboration with Prof. Sergio Barni (Dipartimento di Biologia Animale, University of Pavia). Finally, the authors express their gratitude to Dr. Stan Fakan (Center of Electron Microscopy, University of Lausanne) and Dr. V. Kopeny (Prague, Czech Republic) for helpful comments on the manuscript. This work was supported by grants from the Italian M.U.R.S.T. (COFIN 1998) and the University of Pavia (FAR 1999).


   FOOTNOTES
 
Received for publication April 23, 1999. Revised for publication November 5, 1999.


   REFERENCES
TOP
 ABSTRACT
 INTRODUCTION
 Different conditions, similar...
 HERDS are storage sites...
 RNPs from HERDS may...
 HERDS are morphological markers...
 REFERENCES
 

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