REVIEW
Porifera a reference phylum for evolution and bioprospecting:the power of marine genomics
Werner E.G. Müller, Heiko Schwertner and Isabel M. Müller
Institute for Physiological Chemistry, Department of Applied Molecular Biology, University, Duesbergweg,
Mainz, Germany(Received for publication on March 9, 2004)

Abstract. The term Urmetazoa, as the hypothetical metazoan ancestor, was introduced to highlightthe ﬁnding that all metazoan phyla including the Porifera [sponges] derived from one common ancestor. Analyses of sponge genomes, from Demospongiae, Calcarea and Hexactinellida have permitted
the reconstruction of the evolutionary trail from Fungi to Metazoa. This has provided evidence that thecharacteristic evolutionary novelties of Metazoa existing in Porifera share high sequence similarities
and in some aspects also functional similarities to related polypeptides found in other metazoan phyla.
It is surprising that the genome of Porifera is large and comprises substantially more genes than Protostomia and Deuterostomia. On the basis of solid taxonomy and ecological data, the high value of this
phylum for human application becomes obvious especially with regard to the ﬁeld of chemical ecology
and the hope to ﬁnd novel potential drugs for clinical use. In addition, the beneﬁt of efforts in understanding molecular biodiversity with focus on sponges can be seen in the fact that these animals as‘‘living fossils’’ allow to stethoscope into the past of our globe especially with respect to the evolutionof Metazoa. (Keio J Med 53 (3): 159–165, September 2004)
Key words: evolution, metazoa, Urmetazoa, bioprospecting, bioactive compounds

Introduction

Palaeontology

In the last decade the phylogenetically oldest metazoan phylum, the Porifera (sponges) gained special
interest. Mainly due to the introduction of molecularbiological techniques solid evidence was elaborated
which indicated that this phylum provides a cornucopiaof new information which allows a grasping for the understanding of the dynamics of evolutionary processes
occurring during the Earth period of Ediacara, the timeprior to the Cambrian Explosion which can be dated
back approximately 540 million years ago. Furthermore, the species of this phylum are rich and valuable
sources for bioprospecting, the translation of lifescience discoveries into practical products or processes
for the beneﬁt of the society.

The so far oldest isolated skeletal elements ofsponges, the spicules, were found in China in the Hubei
Province.1 These spicules are monaxones or triaxones
from hexactinellids (glass sponges). These specimens
are dated to the Late Proterozoic age which is stratigraphically equivalent with the Ediacara (South Australia). Since the Early Cambrian (Atdabatian) the
major poriferan taxa, Hexactinellida, Demospongiae,
and Calcarea, have been existent as documented byisolated spicules as well as by more or less completely
preserved sponge fossils, e.g. Solactiniella plumata. The
earliest evidence of the Demospongiae and the Calcarea is the presence of isolated spicules in thin sectionsof rocks from Early Cambrian (Atdabatian).

Presented at the 1344th Meeting of the Keio Medical Society in Tokyo, February 10, 2004.
Reprint requests to: Prof. Dr. W.E.G. Müller, Institut für Physiologische Chemie, Abteilung Angewandte Molekularbiologie, Universität,
Duesbergweg 6, 55099 Mainz, Germany, telephone: +49-6131-39-25910, facsimile: +49-6131-39-25243, e-mail: WMUELLER@UNI-Mainz.DE
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Müller WEG, et al: Porifera a reference phylum

History
The elucidation of the evolutionary origin of metazoans in general and of sponges in particular was problematic since the beginning of modern biology in the
18th century. First Oken (1805) suggested that Metazoa
originated from an ‘‘Urschleim’’ which is composedof Infusoria;2 the unicellular organisms are created byspontaneous generation. Then the ‘‘Gastraea’’-theory
was formulated by Haeckel (1874) who postulated that
Monera are (again) the result of a spontaneous generation from which Amoeba derive and aggregate toMoraea which then develop to Blastaea and ﬁnallyto pelagic Gastraea.3 With respect to Porifera, JamesClark (1867) proposed the ‘‘Choanoﬂagellate’’-theory
which assumes that ﬂagellated Protozoa aggregate to acolonial sponge.4 Even 10 years ago it was still outlinedthat sponges evolve from bioﬁlms, accumulations composed of bacteria, choanoﬂagellates and their secreted
mucus;5 as still cited in modern textbooks sponges are
assumed to be composed of functionally independent
cells.6
The enigmatic relationship of Porifera to other multicellular animals was frequently studied but could
only be resolved by application of gene cloning. Earlier,these species were grouped to plants or to animals; as‘‘Zoophyta’’ or ‘‘Thierpﬂanzen’’.7,8 Not knowing theluxury of sponge genes and their cell-cell-, cell-matrix
receptors and the signal transduction pathways originating from these receptors the sponges were grouped
to the Parazoa [‘‘almost’’ or ‘‘near’’ animals].9
The introduction of molecular cloning of genes, coding for informational proteins increased in a rapid, selfaccelerating manner our knowledge on the evolution to
the Porifera. It furthermore facilitated the subdivisionof this phylum into the three classes, the Hexactinellida,
the Demospongiae and the Calcarea. The ﬁrst reportin line with this new strategy was on the cloning of agalectin from the demosponge Geodia cydonium.10,11
This protein is known to be crucially important for cellcell interactions;12 the deduced sponge protein showed
high sequence similarity to the corresponding galectinsof other metazoan taxa and no relationship to proteinsfrom other kingdoms. Following this strategy, a numberof subsequent publications13,14 clearly demonstrated
that the Porifera have to be grouped together with theother metazoan phyla into one monophyletic unit.15,16
The hypothetical ancestor of all metazoan phyla was ﬁnally named Urmetazoa (Fig. 1).17,18
Molecular Evolution
It is generally agreed that multicellularity in Plantae,
Fungi and Metazoa arose in the Proterozoic approximately 1,000 million years ago. The Porifera evolved as

the earliest Metazoa, with the three major taxa: Hexactinellida, Demospongiae and Calcarea. Our group
has analyzed genes of sponges in order to obtain an insight into the genome organization as well as the function of genes coding for functional proteins. In detail,genes from Demospongiae, Suberites domuncula andGeodia cydonium, from Calcarea, Sycon raphanus, aswell as from Hexactinellida, Aphrocallistes vastus andRhabdocalyptus dawsoni, have been analyzed and theresults were used to describe the hypothetical ancestral
Metazoa, the Urmetazoa (Fig. 1). The study of several
sequences of informative molecules, as housekeeping
proteins, e.g. heat shock protein or b-tubulin,19 proteins
involved in signal transduction, e.g. Ser/Thr kinase20 or
calmodulin,19 from the three poriferan classes, revealed
that the Hexactinellida is the phylogenetically oldest
taxon, while Calcarea is the class closest related tohigher metazoan phyla (Fig. 1).
Based on calculations described earlier it has beenoutlined that the transition to multicellularity took placeabout 1,000 million years ago.19 Later in evolution, 700
million years ago, the green algae evolved, while theﬁrst sponge fossils have been dated back at least to 580
million years ago. Hence, sponges lived more than 30
to 50 million years before the Cambrian Explosion, thetime of main divergence of metazoan phyla. This conclusion is supported by calculations based on the extent
of aa substitutions of two galectins from G. cydonium.
It had been found that these molecules diverged fromthe galectin isolated from the nematode C. elegans, approximately 800 million years ago.10,11 Furthermore,data especially from studies with a series of Ser/Thr
kinases suggested that the Calcarea might be a sistergroup to higher metazoan phyla (Fig. 1).21 The
branching order originating from ancestral unicellular
eukaryotes via Viridiplantae-Fungi to Porifera, thesimplest metazoans, follows both the published fossil
data and the sequence data obtained.
Structural Features of the Sponge Bauplan
Sponges, as the oldest still extant metazoan phylum
are characterized by a simple Bauplan. They are ﬁlterfeeding organisms that are usually sessile. Their bodyis composed of an epithelial layer which surrounds a
mesogleal compartment, the mesohyl; this is reticulated
in a highly organized manner by a canal system.
Molecules involved in cell-cell interaction
Sponges have become a classical model for basic
studies to understand metazoan cell-cell adhesion. It
was Wilson22 who introduced this system in experimental biology which then became a traditional model
to study both cell-cell- and cell-matrix adhesion.23 With

Keio J Med 2004; 53 (3): 159–165

161

Fig. 1 Phylogenetic position of the Porifera, as ‘‘living fossils’’ between the Urmetazoa and the Urbilateria which gave rise to the Protostomia(example: horseshoe crab [K. Takizawa (1879)]) and Deuterostomia (example: fugu ﬁsh [K. Takizawa (1879)]). The major evolutionary novelties which have to be attributed to the Urmetazoa are those molecules which are highlighted. Sponges use secondary metabolites for theirprotection; these compounds became shaped and hence more potent and more speciﬁc during their long evolutionary history.

the isolation of a galectin sequence as the ﬁrst cell-celladhesion molecule,10 and with the integrin sequence as
the ﬁrst cell-matrix adhesion receptor in the demosponge
G. cydonium,24,25 it became overt that sponges containhighly related molecules known to also promote adhesion in Protostomia and Deuterostomia. Sequence
analyses of the galectin cloned from G. cydonium
revealed that those aa residues which are involved inbinding of galectins from mammalians to galactose arealso conserved in the sponge sequence.10 The putative
aggregation receptor was cloned from G. cydonium andfound to comprise fourteen scavenger receptor cysteine-rich domains, six short consensus repeats, a Cterminal transmembrane domain and a cytoplasmic
tail.26

Molecules involved in cell-substrate interaction
The dominant molecule present in the extracellularmatrix of sponges which functions as a cell-matrix adhesion molecule is collagen. The corresponding gene
was cloned both from the freshwater sponge Ephydatia
muelleri27 as well as from the demosponge S. domuncula (Schröder et al., 2000).28 Cell surface-spanning
receptors, in particular the single- as well as the sevenpass transmembrane receptor proteins, serve as receivers for extracellular signaling molecules. Also thesemolecules could be identiﬁed in sponges. The ﬁrst, 1transmembrane receptor (1-TMR) which represents an
autapomorphic character for Metazoa, was the receptor
tyrosine kinase.29 Interestingly the tyrosine dephos-

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phorylating enzymes, the protein-tyrosine phosphatases, exist already in yeasts.30 As a 7-transmembrane
receptor (7-TMR) the metabotropic glutamate/GABAlike receptor was characterized in G. cydonium;31 it
was found to respond to extracellular agonists as wellas antagonists known from metabotropic glutamate/
GABA-like receptors present on nerve cells frommammals.31,32
Molecules involved in morphogenesis
Two classes of proteins are addressed here, themorphogens and the transcription factors. In theextracellular space of sponges morphogens have been
identiﬁed, e.g. the endothelial-monocyte-activating
polypeptide or myotrophin.28,33 Both are very likely
involved in the organization/differentiation of cells
within the sponge body.
Transcription factors
During development of animals, a set of genes, mostof them transcription factors, that are responsible forcell fate and pattern determination, is expressed.
Among them, T-box, Forkhead and Homeobox genefamilies have been found to be extremely conserved,
on sequence and functional level. Among the T-box
family, Brachyury is involved in the formation and differentiation of the third germ layer, the mesoderm, in
tripoblastic animals. Recently, two T-box genes havebeen isolated from the sponge S. domuncula; a Brachyury gene and a homologue of the Tbx2-3-4-5 genes
from chordates, which, interestingly, are involved in theformation of the limbs.34 Functional studies demonstrated that the expression of the Brachyury gene isupregulated in differentiating sponge cells duringformation of canal-like structures.34 Based on thisobservation we postulate that already in sponges a primordial axis formation is genetically ﬁxed. This assumption was subsequently conﬁrmed by the isolationand phylogenetic characterization of ﬁve members of
the forkhead gene family from the sponge S. domuncula.35,36 Forkhead proteins form a subfamily within
the large group of helix-turn-helix proteins. They are
responsible for a wide range of functions and key roles
in early developmental processes, during organogenesis
and also for the function of the major organs and tissues
in the adult animals.
Transcription factors: homeodomain molecules
The developmental processes resulting in the formation of a body axis require a head center; e.g. in bilaterians, the Spemann’s organizer.37 The genes which
are involved in the establishment of the head organizerMüller WEG, et al: Porifera a reference phylum

during embryogenesis have been grouped into threeclasses of homeobox genes, the Paired-class, theAntennapedia-class and the Lim-class genes.38 Also inthis area a strong progress was made in sponges in thelast few years. A paired-class (Pax-2/5/8)-gene had been
isolated from the freshwater sponge Ephydatia ﬂuviatilis,39 which encodes a complete although substantiallydegenerated homeodomain. In S. domuncula a cDNA
encoding a LIM/homeobox protein has been isolated
which comprises high sequence similarity to the related
LIM homeodomain proteins in other animals.40
Genes in S. domuncula indicative for Wnt signaling
The Wnt signaling pathway is a cell communication
system which regulates cell-fate decisions, tissue polarity and morphogenesis. The Frizzled protein is themembrane receptor for the Wnt secreted glycoproteins.
Through the canonical Wnt signaling pathway, theactivated Frizzled binds to Dishevelled (Dsh), whichleads to the stabilization and accumulation of b-cateninin the nucleus, where it activates the TCF/LEF transcription factor. Very recently we isolated the geneencoding the Frizzled receptor from S. domuncula.41 In
situ hybridization analysis in adult specimens demonstrated its expression in the cortex region and in theepithelial layer of the aquiferous canals. The ﬁndings
suggest that a Wnt-pathway involved in cell-fate determination and morphogenesis was already established in
the phylogenetically oldest metazoans, the sponges.
Molecules present in tight junctions
Our screening for a gene encoding a tight junction
scaffold protein from a sponge, here S. domuncula, wassuccessful; the scaffold protein membrane-associatedguanylate kinase with inverted arrangement (MAGI)
had been identiﬁed.34 In addition, the existence of one
tetraspan receptor, tetraspanin, in S. domuncula has
been reported. The tetraspanins belong to a group ofhydrophobic proteins, comprising four transmembrane
domains with a series of conserved aa residues in theextracellular loops.
Bioprospecting
The ﬁeld of bioprospecting of Porifera may be oftremendous potential beneﬁt for humans from the applied point of view. Taking into account that the chemical diversity of natural bioactive compounds is muchhigher than that of compounds synthesized in a standard combinatorial chemistry approaches, and thatnatural compounds display an impressive selectivity,
the high value of the secondary metabolites from natural resources in general and from sponges in particularKeio J Med 2004; 53 (3): 159–165

can only be roughly imagined.42 It is also conceivablethat especially during ﬁrst screening programs aimed to
discover new lead molecules which are directed against
newly discovered targets, the natural compounds aresuperior to those generated by combinatorial chemistry.43 Evolution has designed during 800 million years
the optimal bioactive compound against a particularorganismic disorder. On this background the highly
diverse chemical compounds from sponges which are
likewise provided with a diverse bioactivity are extremely valuable. This exiting research ﬁeld was pioneered by Bergmann and Scheuer.44,45
The diversity of secondary metabolites producedin sponges has been highlighted in a large number ofreviews.46,47 They range from derivatives of aminoacids and nucleosides to macrolides, porphyrins, terpenoids to aliphatic cyclic peroxides and sterols. This
diversity reﬂects the efﬁcient mechanisms of combinatorial biochemistry which the animals have acquired
during their evolutionary history. The question arises ifsponges being the host of associated/symbiotic bacteria
are the real producers or whether the microorganisms
which they harbor produce these substances. Recent
data strongly favor the view that the microorganisms
are the main producers of the natural products which
are subsequently stored and accumulated in the sponge
as chemical defense, although sponge metabolites canalso be produced by speciﬁc sponge cells. As an example the phosphatase inhibitor okadaic acid can becited.48 This compound was ﬁrst isolated from thesponge Halichondria okadai and later found to be produced by the free-living microalgae Prorocentrum limaand perhaps even by bacteria which are associated withthem.49
Very promising is the potential application of bioactive compounds from Porifera in human therapy,
however, their use is limited by the difﬁculty to obtain
sufﬁcient supply of the respective sponge species. Until
now only in one case a bioactive compound fromsponges is applied in clinics, arabinofuranosyladenine(ara-A) as antiviral drug;50 ara-A is a derivative of alead structure isolated from a sponge.44 This drug isused as an anti-Herpes Simplex virus drug; e.g. in Japan
it is the most applied ointment against this disease[Arasena-A2 (Mochida Pharmaceutical Co; Tokyo)].
The Future: Evochemistry
Thanks to the progress initiated by the pressure of
the society for a sustainable use of natural resources forhuman beneﬁt, the exploitation of natural biodiversity
became possible through the application of the techniques of molecular biology and modern cell biology. It
appears to be enigmatic why Porifera and also otherphylogenetically old taxa, all of them being sessile ﬁlter

163

feeders, have been so successful during the long evolutionary period of 800 million years. Answers have been
given in the last two years. As summarized the expected
number of genes in the sponge genome might be>100,000.51 This number is comparatively large; thehuman genome contains A 35,000 genes; Caenorhabditis elegans (nematode [worm]) A 19,000, the insect Drosophila melanogaster A 14,000 and the yeast
Saccharomyces cerevisiae 6,000 genes (Fig. 2). Two major conclusions must be drawn: Firstly, during thetransition from Yeast to the Urmetazoa a period ofdramatic gene duplication must have occurred andSecondly, during the period of evolution from theUrmetazoa to the Protostomia [C. elegans and D. melanogaster] and the Deuterostomia [Homo sapiens] a
reduction of the number of genes must have takenplace. In parallel with the metazoan evolution by loss ofgenes [domains and families] a second evolutionary
progress, which occurred after the Urmetazoa, must be
postulated for the metazoan phyla, an evolution by diversiﬁcation of gene families. The hypothetical Urmetazoa has been proposed as the last common ancestor for
all Metazoa.
The ﬁnding that the number of sponge genes ishigher than that in the ‘‘crown’’ phyla allows also
an explanation why the diversity of the secondary
metabolites in sponges and other ﬁlter feeders is socomparably high. These animals had – in order to survive the environmental threats – to form bioactive
compounds from the ‘‘regular’’ metabolites, the secondary metabolites. During their long evolutionary
history the biological/defensive/pharmacological effectiveness of these compounds were trimmed for higher
potency and selectivity (evochemistry). In consequence,
the richness of the sessile ﬁlter feeders in bioactive
compounds is due to their growth and nutrition characteristics and their comparably large genetic repertoire(Fig. 2).
Conclusion
It is a fortune that, according to the fossil records,
the phylogenetic oldest metazoan phylum, the Porifera
did not become extinct during the last 800 million years.
By analyzing their genetic diversity it became obviousthat all Metazoa originated from one common ancestor,
the Urmetazoa. With respect to the functional aspect
it could be demonstrated that the degree of complexityof the Porifera is beyond any expectations. It becomes
now increasingly obvious that they are provided withmost of the metabolic pathways and genetic elements
required for constructing a metazoan Bauplan.52 Finally it should be stressed that the potential commercial
value of sponge biodiversity is of an unpredictablescale. A new application ﬁeld which very likely will

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Müller WEG, et al: Porifera a reference phylum

Fig. 2 Proposed evolutionary processes proceeding from Yeast to Urmetazoa and subsequently from this hypothetical ancestor of Metazoa to
the Deuterostomia [Homo sapiens] and Protostomia [Caenorhabditis elegans and in Drosophila melanogaster]. It is proposed that the number ofgenes, calculated to be present in sponges and – very likely also in Urmetazoa – has been created by gene duplication. This dramatic increase ingene number was presumably caused by symbionts (e.g. bacteria) which put evolutionary pressure on the host to diversify its gene complexity.
During this process also new domains were formed which gave rise to novel mosaic proteins. In the metazoan phyla, derived from the Urmetazoa, the number of genes decreased by elimination of gene families and in parallel the remaining gene families diversiﬁed. Based upon thehigher gene complexity in the lower metazoan phyla also their potency to synthesize a more complex spectrum of bioactive compounds became
possible.

have a considerable impact in biotechnology is thequestion of the synthesis of bioactive, low-molecularweight compounds in a recombinant manner. To reachthis goals both the gene cluster required for the synthesis of these compounds from the sponge host and theassociated symbiotic bacteria have to be isolated andexpressed in a heterologous system.
Acknowledgements: This work was supported by a grant from theDeutsche Forschungsgemeinschaft, the Bundesministerium für Bildung und Forschung (project: Center of Excellence BIOTECmarin)
and the Deutsche Forschungsgemeinschaft and the International Human Frontier Science Program (RG-333/96-M).

References
1. Mehl D, Müller I, Müller WEG: Molecular biological andpalaeontological evidence that Eumetazoa, including Porifera(sponges), are of monophyletic origin. In: Watanabe Y, Fusetani
N, eds, Sponge Sciences: Multidisciplinary Perspectives,
Springer-Verlag, Tokyo. 1998; 133–156
2. Oken L: Die Zeugung. Bamberg, Joseph A Goebhardt, 1805 (inGerman)3. Haeckel E: Die Gastraea-Theorie, die phylogenetische Classiﬁcation des Thierreichs und die Homologie der Keimblätter.
Jenaische Z f Naturwiss 1874; 8: 1–55 (in German)
4. James-Clark H: Sponge ciliatae as infusoria ﬂagellata. Memoirs
Boston Society of Natural History 1867; 1: 305–340

5. Reitner J, Schumann-Kindel G, Thiel V: Origin and early fossil
record of sponges: a geobiological approach. Memoirs of the
Queensland Museum 1999; 44: 515
6. Pechenik JA: Biology of the Invertebrates, Boston, McGraw
Hill, 2000
7. Donati V: Auszug seiner Natur-Geschichte des Adriatischen
Meeres, Halle, Francken, 1753 (in German)
8. Pallas PS: Charakteristik der Thierpﬂanzen, Nürnberg, Raspiche
Buchhandlung, 1787 (in German)
9. Westheide W, Rieger R: Spezielle Zoologie; part 1, Stuttgart,
Gustav Fischer Verlag, 1996 (in German)
10. Pfeifer K, Haasemann M, Gamulin V, Bretting H, Fahrenholz F,
Müller WE: S-type lectins occur also in invertebrates: high conservation of the carbohydrate recognition domain in the lectin
genes from the marine sponge Geodia cydonium. Glycobiology
1993; 3: 179–184
11. Pfeifer K, Haasemann M, Gamulin V, Bretting H, Fahrenholz F,
Müller WE: S-type lectins occur also in invertebrates: high conservation of the carbohydrate recognition domain in the lectin
genes from the marine sponge Geodia cydonium. Glycobiology
1993; 3: 179–184
12. Hirabayashi J, Kasai K: The family of metazoan metalindependent beta-galactoside-binding lectins: structure, function
and molecular evolution. Glycobiology 1993; 3: 297–304
13. Müller WEG: Molecular Evolution: Evidence for Monophyly of
Metazoa, New York, Springer Verlag, 1998 (Progress in molecular and subcellular biology; 19)
14. Müller WEG: Molecular Evolution: Towards the Origin of Metazoa, New York, Springer Verlag, 1998 (Progress in molecularand subcellular biology; 21)
15. Müller WE, Müller IM, Gamulin V: On the monophyletic

Keio J Med 2004; 53 (3): 159–165

16.
17.

18.

19.

20.

21.

22.
23.
24.

25.

26.

27.

28.

29.

30.

31.

32.

evolution of the metazoa. Braz J Med Biol Res 1994; 27: 2083–
2096
Müller WE: Molecular phylogeny of Metazoa (animals): monophyletic origin. Naturwissenschaften 1995; 82: 321–329
Müller WE: Review: How was metazoan threshold crossed? The
hypothetical Urmetazoa. Comp Biochem Physiol A Mol Integr
Physiol 2001; 129: 433–460
Müller WE, Schröder HC, Skorokhod A, Bunz C, Müller IM,
Grebenjuk VA: Contribution of sponge genes to unravel the
genome of the hypothetical ancestor of Metazoa (Urmetazoa).
Gene 2001; 276: 161–173
Schutze J, Krasko A, Custodio MR, Efremova SM, Müller IM,
Müller WE: Evolutionary relationships of Metazoa within the
eukaryotes based on molecular data from Porifera. Proc R Soc
Lond B Biol Sci 1999; 266: 63–73
Kruse M, Leys SP, Müller IM, Müller WE: Phylogenetic positionof the Hexactinellida within the phylum Porifera based on theamino acid sequence of the protein kinase C from Rhabdocalyptus dawsoni. J Mol Evol 1998; 46: 721–728
Müller WE, Kruse M, Koziol C, Müller JM, Leys SP: Evolutionof early Metazoa: phylogenetic status of the Hexactinellida
within the phylum of Porifera (sponges). Prog Mol Subcell Biol
1998; 21: 141–156
Wilson HV: On some phenomena of coalescence and regeneration in sponges. J Exptl Zool 1907; 5: 245–258
Müller WEG: Cell membranes in sponges. Intern Rev Cytol
1982; 77: 129–181
Pancer Z, Kruse M, Müller I, Müller WE: On the origin of Metazoan adhesion receptors: cloning of integrin alpha subunit fromthe sponge Geodia cydonium. Mol Biol Evol 1997; 14: 391–398
Wimmer W, Blumbach B, Diehl-Seifert B, Koziol C, Batel
R, Steffen R, Müller IM, Müller WE: Increased expression of
integrin and receptor tyrosine kinase genes during autograft fusion in the sponge Geodia cydonium. Cell Adhes Commun 1999;
7: 111–124
Blumbach B, Pancer Z, Diehl-Seifert B, Steffen R, Münkner J,
Müller I, Müller WE: The putative sponge aggregation receptor.
Isolation and characterization of a molecule composed of scavenger receptor cysteine-rich domains and short consensus
repeats. J Cell Sci 1998; 111: 2635–2644
Exposito JY, Garrone R: Characterization of a ﬁbrillar collagengene in sponges reveals the early evolutionary appearance of
two collagen gene families. Proc Natl Acad Sci USA 1990; 87:
6669–6673
Schröder HC, Krasko A, Batel R, Skorokhod A, Pahler S, Kruse
M, Müller IM, Müller WE: Stimulation of protein (collagen)synthesis in sponge cells by a cardiac myotrophin-related molecule from Suberites domuncula. FASEB J 2000; 14: 2022–2031
Müller WE, Schäcke H: Characterization of the receptor
protein-tyrosine kinase gene from the marine sponge Geodia
cydonium. Prog Mol Subcell Biol 1996; 17: 183–208
Müller CI, Blumbach B, Krasko A, Schröder HC: Receptor
protein-tyrosine phosphatases: origin of domains (catalytic domain, Ig-related domain, ﬁbronectin type III module) based on
the sequence of the sponge Geodia cydonium. Gene 2001; 262:
221–230
Perovic S, Krasko A, Prokic I, Müller IM, Müller WE: Origin ofneuronal-like receptors in Metazoa: cloning of a metabotropic
glutamate/GABA-like receptor from the marine sponge Geodia
cydonium. Cell Tissue Res 1999; 296: 395–404
Kaupmann K, Huggel K, Heid J, Flor PJ, Bischoff S, Mickel
SJ, McMaster G, Angst C, Bittiger H, Froestl W, Bettler B:
Expression cloning of GABA(B) receptors uncovers similarity
to metabotropic glutamate receptors. Nature 1997; 386: 239–
246

165
33. Pahler S, Krasko A, Schutze J, Müller IM, Müller WE: Isolationand characterization of a cDNA encoding a potential morphogen
from the marine sponge Geodia cydonium that is conserved inhigher metazoans. Proc R Soc Lond B Biol Sci. 1998; 265: 421–
425
34. Adell T, Nefkens I, Müller WE: Polarity factor ‘Frizzled’ in thedemosponge Suberites domuncula: identiﬁcation, expression andlocalization of the receptor in the epithelium/pinacoderm(1).
FEBS Lett 2003; 554: 363–368
35. Adell T, Wiens M, Müller WEG: Sd-Bra and SD-Tbx: ﬁrst T-box
transcription factors from Porifera. Boll Mus Ist Biol Univ Genova 2002; 66/67: 5
36. Adell T, Müller WEG: Isolation and characterization of ﬁve
Forkhead genes from the sponge Suberites domuncula. Gene
2004; 334: 35–46
37. Spemann H: Experimentelle Beiträge zu einer Theorie derEntwicklung. Berlin, Springer Verlag, 1936 (in German)
38. Galliot B, Miller D: Origin of anterior patterning. How old is ourhead? Trends Genet 2000; 16: 1–5
39. Hoshiyama D, Suga H, Iwabe N, Koyanagi M, Nikoh N, Kuma
K, Matsuda F, Honjo T, Miyata T: Sponge Pax cDNA related toPax-2/5/8 and ancient gene duplications in the Pax family. J Mol
Evol 1998; 47: 640–648
40. Wiens M, Mangoni A, D’Esposito M, Fattorusso E, Korchagina
N, Schröder HC, Grebenjuk VA, Krasko A, Batel R, Müller IM,
Müller WE: The molecular basis for the evolution of the metazoan bodyplan: extracellular matrix-mediated morphogenesis inmarine demosponges. J Mol Evol 2003; 57: S60–75
41. Adell T, Grebenjuk VA, Wiens M, Müller WE: Isolation andcharacterization of two T-box genes from sponges, the phylogenetically oldest metazoan taxon. Dev Genes Evol. 2003; 213:
421–434
42. Wessjohann LA: Synthesis of natural-product-based compound
libraries. Curr Opin Chem Biol 2000; 4: 303–309
43. Harvey A: Strategies for discovering drugs from previously
unexplored natural products. Drug Discov Today 2000; 5: 294–300
44. Bergmann W, Feeney RJ: Contribution to the study of marine
sponges. 32, the nucleosides of sponges. J Org Chem 1951; 16:
981–987
45. Scheuer PJ: Some marine ecological phenomena: chemical basis
and biomedical potential. Science 1990; 248: 173–177
46. Faulkner DJ: Marine natural products. Nat Prod Rep 1995; 13:
259–302
47. Sarma AS, Daum T, Müller WEG: Secondary Metabolites from
Marine Sponges, Berlin, Ullstein-Mosby Verlag, 1993
48. Tachibana K, Scheuer PJ, Tsukitani Y, Kikushi H, Engen DV,
Clardy J, Gopichand Y, Schmitz FJ: Okadaic acid a cytotoxic
polyether from the marine sponges of the genus Halichondria. J
Am Chem Soc 1981; 103: 2469–2471
49. Murakami Y, Oshima Y, Yasumoto T: Identiﬁcation of okadaicacid as a toxic component of a marine dinoﬂagellate Prorocentrum lima. Nihon Suisan Gakkaishi 1982; 48: 69–72
50. Müller WE, Zahn RK, Bittlingmaier K, Falke D: Inhibitionof herpesvirus DNA synthesis by 9-beta-D-arabinofuranosyladenine in cellular and cell-free systems. Ann N Y Acad Sci
1977; 284: 34–48
51. Breter HJ, Grebenjuk VA, Skorokhod A, Müller WEG: Approaches for a sustainable use of the bioactive potential insponges: analysis of gene clusters, differential display of mRNAand DNA chips. In: Müller WEG, ed, Sponges (Porifera). Marine Molecular Biotechnology, Berlin, Springer, 2003: 199–230
52. Müller WE, Krasko A, Le Pennec G, Schröder HC: Biochemistry and cell biology of silica formation in sponges. Microsc Res
Tech 2003; 62: 368–377