The pancreas contains both exocrine and endocrine cells, but the molecular mechanisms controlling the differentiation of these cell types are largely unknown. Despite their endodermal origin, pancreatic endocrine cells share several molecular characteristics with neurons, and, like neurons in the central nervous system, differentiating endocrine cells in the pancreas appear in a scattered fashion within a field of progenitor cells. This indicates that they may be generated by lateral specification through Notch signalling. Here, to test this idea, we analysed pancreas development in mice genetically altered at several steps in the Notch signalling pathway. Mice deficient for Delta-like gene 1 (Dll1) or the intracellular mediator RBP-JK showed accelerated differentiation of pancreatic endocrine cells. A similar phenotype was observed in mice over-expressing neurogenin 3(ngn 3) or the intracellular form of Notch3 (ref. 13) (a repressor of Notch signalling). These data provide evidence that ngn3 acts as pro-endocrine gene and that Notch signalling is critical for the decision between theendocrine and progenitor/exocrine fates in the developing pancreas.

Notch signalling controls pancreatic cell differentiation

Choanoflagellates are the closest known relatives of metazoans. To discover potential molecular mechanisms underlying the evolution of metazoan multicellularity, we sequenced and analysed the genome of the unicellular choanoflagellate Monosiga brevicollis. The genome contains approximately 9,200 intron-rich genes, including a number that encode cell adhesion and signalling protein domains that are otherwise restricted to metazoans. Here we show that the physical linkages among protein domains often differ between M. brevicollis and metazoans, suggesting that abundant domain shuffling followed the separation of the choanoflagellate and metazoan lineages. The completion of the M. brevicollis genome allows us to reconstruct with increasing resolution the genomic changes that accompanied the origin of metazoans.

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The genome of the choanoflagellate Monosiga brevicollis and the origin of metazoans.

▪ Abstract Over 35 years ago, Susumu Ohno stated that gene duplication was the single most important factor in evolution (97). He reiterated this point a few years later in proposing that without duplicated genes the creation of metazoans, vertebrates, and mammals from unicellular organisms would have been impossible. Such big leaps in evolution, he argued, required the creation of new gene loci with previously nonexistent functions (98). Bold statements such as these, combined with his proposal that at least one whole-genome duplication event facilitated the evolution of vertebrates, have made Ohno an icon in the literature on genome evolution. However, discussion on the occurrence and consequences of gene and genome duplication events has a much longer, and often neglected, history. Here we review literature dealing with the occurence and consequences of gene duplication, begining in 1911. We document conceptual and technological advances in gene duplication research from this early research in comparat...

/pdf/duplication-and-divergence-the-evolution-of-new-genes-and-5blj5mai9u.pdf

Duplication and Divergence: The Evolution of New Genes and Old Ideas

Tapeworms (Cestoda) cause neglected diseases that can be fatal and are difficult to treat, owing to inefficient drugs. Here we present an analysis of tapeworm genome sequences using the human-infective species Echinococcus multilocularis, E. granulosus, Taenia solium and the laboratory model Hymenolepis microstoma as examples. The 115- to 141-megabase genomes offer insights into the evolution of parasitism. Synteny is maintained with distantly related blood flukes but we find extreme losses of genes and pathways that are ubiquitous in other animals, including 34 homeobox families and several determinants of stem cell fate. Tapeworms have specialized detoxification pathways, metabolism that is finely tuned to rely on nutrients scavenged from their hosts, and species-specific expansions of non-canonical heat shock proteins and families of known antigens. We identify new potential drug targets, including some on which existing pharmaceuticals may act. The genomes provide a rich resource to underpin the development of urgently needed treatments and control.

/pdf/the-genomes-of-four-tapeworm-species-reveal-adaptations-to-8ztummdxvw.pdf

The genomes of four tapeworm species reveal adaptations to parasitism

Hedgehog proteins constitute one of a small number of families of secreted signals that have a central role in the development of metazoans. Genetic analyses in flies, fish and mice have uncovered the major components of the pathway that transduces Hedgehog signals, and recent genome sequence projects have provided clues about its evolutionary origins. In this Review we provide an updated overview of the mechanisms and functions of this signalling pathway, highlighting the conserved and divergent features of the pathway, as well as some of the common themes in its deployment that have emerged from recent studies.

Mechanisms and functions of Hedgehog signalling across the metazoa

Genes of the Hox cluster are restricted to the animal kingdom and play a central role in axial patterning in divergent animal phyla1. Despite its evolutionary and developmental significance, the origin of the Hox gene cluster is obscure. The consensus is that a primordial Hox cluster arose by tandem gene duplication close to animal origins2,3,4,5. Several homeobox genes with high sequence identity to Hox genes are found outside the Hox cluster and are known as ‘dispersed’ Hox-like genes; these genes may have been transposed away from an expanding cluster6. Here we show that three of these dispersed homeobox genes form a novel gene cluster in the cephalochordate amphioxus. We argue that this ‘ParaHox’ gene cluster is an ancient paralogue (evolutionary sister) of the Hox gene cluster; the two gene clusters arose by duplication of a ProtoHox gene cluster. Furthermore, we show that amphioxus ParaHox genes have co-linear developmental expression patterns in anterior, middle and posterior tissues. We propose that the origin of distinct Hox and ParaHox genes by gene-cluster duplication facilitated an increase in body complexity during the Cambrian explosion.

The ParaHox gene cluster is an evolutionary sister of the Hox gene cluster

The HB9 homeobox gene has been clonedfrom several vertebrates and is implicated in motor neurondifferentiation. In the chick, a related gene,MNR2, actsupstream ofHB9 in this process. Here we report anamphioxus homologue of these genes and show that itdiverged before the gene duplication yieldingHB9 andMNR2. AmphiMnx RNA is detected in two irregularpunctate stripes along the developing neural tube, com-parable to the distribution of ‘dorsal compartment’ motorneurons, and also in dorsal endoderm and posteriormesoderm. We propose a new homeobox class, Mnx, toinclude AmphiMnx, HB9, MNR2 and theirDrosophilaand echinoderm orthologues; we suggest that vertebrateHB9 is renamed Mnx1 and MNR2 be renamed Mnx2.Keywords Homeobox · Motor neuron · Amphioxus ·Gene duplication Introduction The HB9 homeobox gene (also known asHLXB9) wasfirst isolated in humans (Deguchi and Kehrl 1991) andsubsequently in other vertebrates (Saha et al. 1997;Tanabe et al. 1998; Harrison et al. 1999).HB9 is marginallymore closely related to Hox, ParaHox, En, Emx, and NKclass homeobox genes than it is to the Prd, Prd-like ormore divergent homeobox classes (Burglin 1994). Itsevolutionary origin is unclear, however. One early sug-gestion was thatHB9 is related to, or derived from, theDrosophila homeotic geneproboscipedia (Burglin 1994;Harrison et al. 1994). This now seems unlikely asHB9maps to 7q36 (nearEn2 and Gbx1) and not within thehuman Hox clusters (Pollard and Holland 2000). An alter-native possibility is thatHB9 is a member of a distinctclass of homeobox genes, analogous to other definedclasses such as Emx, Msx, Dlx, Mox, etc. Consistent withthis suggestion, a second homeobox gene with highsequence identity toHB9 over the homeobox was reportedfrom chick, and namedMNR2 (Tanabe et al. 1998). Inter-estingly, MNR2 and HB9 are both expressed during motorneuron differentiation, and form part of a cascade of genesregulating this process (Tanabe et al. 1998; Arber et al.1999). HB9 is also expressed in the developing gut, brain,testis and lymphoid lineage (Harrison et al. 1994, 1999;Saha et al. 1997) and mutations inHB9 are implicated inthe human congenital condition sacral agenesis (Lynch etal. 1995; Ross et al. 1998). To investigate the relatednessbetween HB9 and MNR2, and the evolution of their devel-opmental roles, we have examined a homologous gene ina cephalochordate (amphioxus), the group of animalsthought to be the sister group of the vertebrates.

The Mnx homeobox gene class defined by HB9, MNR2 and amphioxus AmphiMnx

Hedgehog proteins are important cell–cell signalling proteins utilized during the development of multicellular animals. Members of the hedgehog gene family have not been detected outside the Metazoa, raising unanswered questions about their evolutionary origin. Here we report a highly unusual hedgehog-related gene from a choanoflagellate, a close unicellular relative of the animals. The deduced C-terminal domain, Hoglet-C, is homologous to the autocatalytic domain of Hedgehog proteins and is predicted to function in autocatalytic cleavage of the precursor peptide. In contrast, the N-terminal Hoglet-N peptide has no similarity to the signalling peptide of Hedgehog (Hh-N). Instead, Hoglet-N is deduced to be a secreted protein with an enormous threonine-rich domain of unprecedented size and purity (over 200 threonine residues) and two polysaccharide-binding domains. Structural modelling reveals that these domains have a novel combination of features found in cellulose-binding domains (CBD) of types IIa and IIb, and are expected to bind cellulose. We propose that the two CBD domains enable Hoglet-N to bind to plant matter, tethering an amorphous nucleophilic anchor, facilitating transient adhesion of the choanoflagellate cell. Since Hh-C and Hoglet-C are homologous, but Hh-N and Hoglet-N are not, we argue that metazoan hedgehog genes evolved by fusion of two distinct genes.

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Nina M. Brooke

Papers

The ParaHox gene cluster is an evolutionary sister of the Hox gene cluster

The Mnx homeobox gene class defined by HB9, MNR2 and amphioxus AmphiMnx

An unusual choanoflagellate protein released by Hedgehog autocatalytic processing

The evolution of multicellularity and early animal genomes.