BMC Biology - Latest Articles

Functional divergence of the brain-size regulating gene MCPH1 during primate evolution and the origin of humans

Lei Shi — 2013-05-22T00:00:00Z

Background: One of the key genes that regulate human brain size, MCPH1 has evolved under strongDarwinian positive selection during the evolution of primates. During this evolution, thedivergence of MCPH1 protein sequences among primates may have caused functionalchanges that contribute to brain enlargement. Results: To test this hypothesis, we used co-immunoprecipitation and reporter gene assays to examinethe activating and repressing effects of MCPH1 on a set of its down-stream genes and thencompared the functional outcomes of a series of mutant MCPH1 proteins that carry mutationsat the human- and great-ape-specific sites. The results demonstrate that the regulatory effectsof human MCPH1 and rhesus macaque MCPH1 are different in 3 of 8 down-stream genestested (p73, cyclinE1 and p14ARF), suggesting a functional divergence of MCPH1 betweenhuman and non-human primates. Further analyses of the mutant MCPH1 proteins indicatedthat most of the human-specific mutations could change the regulatory effects on the downstreamgenes. A similar result was also observed for one of the four great-ape-specificmutations. Conclusions: Collectively, we propose that during primate evolution in general and human evolution inparticular, the divergence of MCPH1 protein sequences under Darwinian positive selectionled to functional modifications, providing a possible molecular mechanism of how MCPH1contributed to brain enlargement during primate evolution and human origin.

In pursuit of an HIV vaccine: an interview with Andrew McMichael

Andrew McMichael — 2013-05-21T00:00:00Z

Can the immune system be induced to protect itself against HIV infection? Andrew McMichael gives his perspective in an interview, explaining the challenges faced in making a vaccine and why he remains optimistic about the potential of eliciting strong T cell responses for controlling the virus.

Thirty years on: HIV receptor gymnastics and the prevention of infection

Robin Weiss — 2013-05-21T00:00:00Z

During 30 years of research on human immunodeficiency virus (HIV), our knowledge of its cellular receptors - CD4, CCR5 and CXCR4 - has illuminated aspects of the pathogenesis of the acquired immune deficiency syndrome (AIDS). Studying how the HIV envelope glycoproteins interact with the receptors led to anti-retroviral drugs based on blocking the docking or fusion of virus to the host cell. Genetic polymorphisms of CCR5 determine resistance to HIV infection and the rate of progression to AIDS. Eliciting neutralizing antibodies to the sites of receptor interaction on HIV glycoproteins is a promising approach to HIV vaccine development.

Bacteroides thetaiotaomicron and Faecalibacterium prausnitzii influence the production of mucus glycans and the development of goblet cells in the colonic epithelium of a gnotobiotic model rodent

Laura Wrzosek — 2013-05-21T00:00:00Z

Background: The intestinal mucus layer plays a key role in the maintenance of host-microbiotahomeostasis. To document the crosstalk between the host and microbiota, we usedgnotobiotic models to study the influence of two major commensal bacteria, Bacteroidesthetaiotaomicron and Faecalibacterium prausnitzii, on this intestinal mucus layer. B.thetaiotaomicron is known to use polysaccharides from mucus, but its effect on goblet cellshas not been addressed so far. F. prausnitzii is of particular physiological importance becauseit can be considered as a sensor and a marker of human health. We determined whether B.thetaiotaomicron affected goblet cell differentiation, mucin synthesis and glycosylation in thecolonic epithelium. We then investigated how F. prausnitzii influenced the colonic epithelialresponses to B. thetaiotaomicron. Results: B. thetaiotaomicron, an acetate producer, increased goblet cell differentiation, expression ofmucus-related genes and the ratio of sialylated to sulfated mucins in mono-associated rats. B.thetaiotaomicron therefore stimulates the secretory lineage, favoring mucus production.When B. thetaiotaomicron was associated with F. prausnitzii, an acetate consumer and abutyrate producer, the effects on goblet cells and mucin glycosylation were diminished. F.prausnitzii, by attenuating the effects of B. thetaiotaomicron on mucus, may help theepithelium to maintain appropriate proportions of different cell types of the secretory lineage.Using a mucus-producing cell line, we showed that acetate upregulated KLF4, a transcriptionfactor involved in goblet cell differentiation. Conclusions: B. thetaiotaomicron and F. prausnitzii, which are metabolically complementary, modulate, invivo, the intestinal mucus barrier by modifying goblet cells and mucin glycosylation. Ourstudy reveals the importance of the balance between two main commensal bacteria inmaintaining colonic epithelial homeostasis via their respective effects on mucus.

Q&A: Antibiotic resistance: what more do we know and what more can we do?

Gerard Wright — 2013-05-17T00:00:00Z

Antibiotic resistance is both an ancient phenomenon and a worsening medical problem. Gerard Wright explains why, and what should be done about it.

On the origin of POU5F1

Stephen Frankenberg — 2013-05-09T00:00:00Z

Background: Pluripotency is a fundamental property of early mammalian development but it is currentlyunclear to what extent its cellular mechanisms are conserved in vertebrates or metazoans.POU5F1 and POU2 are the two principle members constituting the class V POU domainfamily of transcription factors, thought to have a conserved role in the regulation ofpluripotency in vertebrates as well as germ cell maintenance and neural patterning. They haveundergone a complex pattern of evolution which is poorly understood and controversial. Results: By analysing the sequences of POU5F1, POU2 and their flanking genes, we provide strongindirect evidence that POU5F1 originated at least as early as a common ancestor ofgnathostomes but became extinct in a common ancestor of teleost fishes, while both POU5F1and POU2 survived in the sarcopterygian lineage leading to tetrapods. Less divergent formsof POU5F1 and POU2 appear to have persisted among cartilaginous fishes. Conclusions: Our study resolves the controversial evolutionary relationship between teleost pou2 andtetrapod POU2 and POU5F1, and shows that class V POU transcription factors have existedat least since the common ancestor of gnathostome vertebrates. It provides a framework forelucidating the basis for the lineage-specific extinctions of POU2 and POU5F1.

Somatic and visceral nervous systems - an ancient duality

Paola Bertucci — 2013-04-30T00:00:00Z

The vertebrate nervous system is deeply divided into ‘somatic’ and ‘visceral’ subsystems that respond to external and internal stimuli, respectively. Molecular characterization of neurons in different groups of mollusks by Nomaksteinsky and colleagues, published in this issue of BMC Biology, reveals that the viscero-somatic duality is evolutionarily ancient, predating Bilateria.See research article: http://www.biomedcentral.com/1741-7007/11/53

Spatial and temporal in vivo analysis of circulating and sessile immune cells in mosquitoes: hemocyte mitosis following infection

Jonas King — 2013-04-30T00:00:00Z

Background: Mosquitoes respond to infection by mounting immune responses. The primary regulators of these immune responses are cells called hemocytes, which kill pathogens via phagocytosis and via the production of soluble antimicrobial factors. Mosquito hemocytes are circulated throughout the hemocoel (body cavity) by the swift flow of hemolymph (blood), and data show that some hemocytes also exist as sessile cells that are attached to tissues. The purpose of this study was to create a quantitative physical map of hemocyte distribution in the mosquito, Anopheles gambiae, and to describe the cellular immune response in an organismal context. Results: Using correlative imaging methods we found that the number of hemocytes in a mosquito decreases with age, but that regardless of age, approximately 75% of the hemocytes occur in circulation and 25% occur as sessile cells. Infection induces an increase in the number of hemocytes, and tubulin and nuclear staining showed that this increase is primarily due to mitosis and, more specifically, autonomous cell division, by circulating granulocytes. The majority of sessile hemocytes are present on the abdominal wall, although significant numbers of hemocytes are also present in the thorax, head, and several of the appendages. Within the abdominal wall, the areas of highest hemocyte density are the periostial regions (regions surrounding the valves of the heart, or ostia), which are ideal locations for pathogen capture as these are areas of high hemolymph flow. Conclusions: These data describe the spatial and temporal distribution of mosquito hemocytes, and map the cellular response to infection throughout the hemocoel.

Ancient origin of somatic and visceral neurons

Marc Nomaksteinsky — 2013-04-30T00:00:00Z

Background: A key to understanding the evolution of the nervous system on a large phylogenetic scale is the identification of homologous neuronal types. Here, we focus this search on the sensory and motor neurons of bilaterians, exploiting their well-defined molecular signatures in vertebrates. Sensorimotor circuits in vertebrates are of two types: somatic (that sense the environment and respond by shaping bodily motions) and visceral (that sense the interior milieu and respond by regulating vital functions). These circuits differ by a small set of largely dedicated transcriptional determinants: Brn3 is expressed in many somatic sensory neurons, first and second order (among which mechanoreceptors are uniquely marked by the Brn3+/Islet1+/Drgx+ signature), somatic motoneurons uniquely co-express Lhx3/4 and Mnx1, while the vast majority of neurons, sensory and motor, involved in respiration, blood circulation or digestion are molecularly defined by their expression and dependence on the pan-visceral determinant Phox2b. Results: We explore the status of the sensorimotor transcriptional code of vertebrates in mollusks, a lophotrochozoa clade that provides a rich repertoire of physiologically identified neurons. In the gastropods Lymnaea stagnalis and Aplysia californica, we show that homologues of Brn3, Drgx, Islet1, Mnx1, Lhx3/4 and Phox2b differentially mark neurons with mechanoreceptive, locomotory and cardiorespiratory functions. Moreover, in the cephalopod Sepia officinalis, we show that Phox2 marks the stellate ganglion (in line with the respiratory — that is, visceral— ancestral role of the mantle, its target organ), while the anterior pedal ganglion, which controls the prehensile and locomotory arms, expresses Mnx. Conclusions: Despite considerable divergence in overall neural architecture, a molecular underpinning for the functional allocation of neurons to interactions with the environment or to homeostasis was inherited from the urbilaterian ancestor by contemporary protostomes and deuterostomes.

Statistical support for the hypothesis of developmental constraint in marsupial skull evolution

C Bennett — 2013-04-26T00:00:00Z

Background: In contrast to placental neonates, in which all cranial bones are ossified, marsupial young have only the bones of the oral region and the exoccipital ossified at birth, in order to facilitate suckling at an early stage of development. In this study, we investigated whether this heterochronic shift in the timing of cranial ossification constrains cranial disparity in marsupials relative to placentals. Methods: We collected three-dimensional (3D) landmark data about the crania of a wide range of extant placentals and marsupials, and from six fossil metatherians (the clade including extant marsupials and their stem relatives), using a laser scanner and a 3D digitizer. Principal components analysis and delta variance tests were used to investigate the distribution and disparity of cranial morphology between different landmark sets (optimizing either number of landmarks or number of taxa) of the whole skull and of individual developmental or functional regions (neurocranium, viscerocranium, oral region) for extant placentals and marsupials. Marsupial and placental data was also compared based on shared ecological aspects including diet, habitat, and time of peak activity. Results: We found that the extant marsupial taxa investigated here occupy a much smaller area of morphospace than the placental taxa, with a significantly (P<0.01) smaller overall variance. Inclusion of fossil taxa did not significantly increase the variance of metatherian cranial shape. Fossil forms generally plotted close to or within the realm of their extant marsupial relatives. When the disparities of cranial regions were investigated separately, significant differences between placentals and marsupials were seen for the viscerocranial and oral regions, but not for the neurocranial region. Conclusion: These results support the hypothesis of developmental constraint limiting the evolution of the marsupial skull, and further suggest that the marsupial viscerocranium as a whole, rather than just the early-ossifying oral region, is developmentally constrained.