The phylotypic stage as a boundary of modular memory: non mechanistic perspective

The concept of the phylotypic stage has been strongly integrated into developmental biology, thanks mostly to drawings presented by Haeckel (Anthropogenie oder Entwicklungsgeschichte des Menschen, 1874). They are printed in every textbook as proof of the existence of the phylotypic stage and the fact of its conservation, albeit many times criticized as misleading and simplifying (Richardson in Develop Biol 172:412-421, 1995, Richardson et al. in Anat Embryo 196:91-106, 1997; Bininda-Emons et al. in Proc R Soc Lond 270:341-346, 2003). Although generally accepted by modern biology, doubt still exists concerning the very existence or the usefulness of the concept. What kind of evolutionary and developmental horizons does it open indeed? This article begins with the history of the concept, discusses its validity and draws this into connotation with the idea of a memory activated throughout the development. Barbieri (The organic codes. An introduction to semantic biology, 2003) considers the phylotypic stage to be a crucial boundary when the genetic program ceases to suffice for further development of the embryo, and supracellular memory of the body plan is activated. This moment clearly coincides with the commencing of the modular development of the embryo. In this article the nature of such putative memory will be discussed.     

Selenium in thioredoxin reductase: a mechanistic perspective

Most high M(r) thioredoxin reductases (TRs) have the unusual feature of utilizing a vicinal disulfide bond (Cys(1)-Cys(2)) which forms an eight-membered ring during the catalytic cycle. Many eukaryotic TRs have replaced the Cys(2) position of the dyad with the rare amino acid selenocysteine (Sec). Here we demonstrate that Cys- and Sec-containing TRs are distinguished by the importance each class of enzymes places on the eight-membered ring structure in the catalytic cycle. This hypothesis was explored by studying the truncated enzyme missing the C-terminal ring structure in conjunction with oxidized peptide substrates to investigate the reduction and opening of this dyad. The peptide substrates were identical in sequence to the missing part of the enzyme, containing either a disulfide or selenylsulfide linkage, but were differentiated by the presence (cyclic) and absence (acyclic) of the ring structure. The ratio of these turnover rates informs that the ring is only of modest importance for the truncated mouse mitochondrial Sec-TR (ring/no ring = 32), while the ring structure is highly important for the truncated Cys-TRs from Drosophila melanogaster and Caenorhabditis elegans (ring/no ring > 1000). All three enzymes exhibit a similar dependence upon leaving group pK(a) as shown by the use of the acyclic peptides as substrates. These two factors can be reconciled for Cys-TRs if the ring functions to simultaneously allow for attack by a nearby thiolate while correctly positioning the leaving group sulfur atom to accept a proton from the enzymic general acid. For Sec-TRs the ring is unimportant because the lower pK(a) of the selenol relative to a thiol obviates its need to be protonated upon S-Se bond scission and permits physical separation of the selenol and the general acid. Further study of the biochemical properties of the truncated Cys and Sec TR enzymes demonstrates that the chemical advantage conferred on the eukaryotic enzyme by a selenol is the ability to function at acidic pH.     

Testing the vulnerability of the phylotypic stage: on modularity and evolutionary conservation

The phylotypic stage is the developmental stage at which vertebrates most resemble each other. In this study we test the plausibility of the hypotheses of Sander [1983, Development and Evolution, Cambridge University Press] and Raff [1994, Early Life on Earth, Columbia University Press; 1996, The Shape of Life, University of Chicago Press] that the phylotypic stage is conserved due to the intense and global interactivity occurring during that stage. First, we test the prediction that the phylotypic stage is much more vulnerable than any other stage. A search of the teratological literature shows that disturbances at this stage lead to a much higher mortality than in other stages, in accordance with the prediction. Second, we test whether that vulnerability is indeed caused by the interactiveness and lack of modularity of the inductions or, alternatively, is caused by some particularly vulnerable process going on at that time. From the pattern of multiple induced anomalies we conclude that it is indeed the interactiveness that is the root cause of the vulnerability. Together these results support the hypotheses of Sander and Raff. We end by presenting an argument on why the absence of modularity in the inductive interactions may also be the root cause of the conservation of the much discussed temporal and spatial colinearity of the Hox genes. J. Exp. Zool. (Mol. Dev. Evol.) 291:195-204, 2001.     

Inverting the hourglass: quantitative evidence against the phylotypic stage in vertebrate development

The concept of a phylotypic stage, when all vertebrate embryos show low phenotypic diversity, is an important cornerstone underlying modern developmental biology. Many theories involving patterns of development, developmental modules, mechanisms of development including developmental integration, and the action of natural selection on embryological stages have been proposed with reference to the phylotypic stage. However, the phylotypic stage has never been precisely defined, or conclusively supported or disproved by comparative quantitative data. We tested the predictions of the 'developmental hourglass' definition of the phylotypic stage quantitatively by looking at the pattern of developmental-timing variation across vertebrates as a whole and within mammals. For both datasets, the results using two different metrics were counter to the predictions of the definition: phenotypic variation between species was highest in the middle of the developmental sequence. This surprising degree of developmental character independence argues against the existence of a phylotypic stage in vertebrates. Instead, we hypothesize that numerous tightly delimited developmental modules exist during the mid-embryonic period. Further, the high level of timing changes (heterochrony) between these modules may be an important evolutionary mechanism giving rise to the diversity of vertebrates. The onus is now clearly on proponents of the phylotypic stage to present both a clear definition of it and quantitative data supporting its existence.     

Retinal neuroprotection by growth factors: a mechanistic perspective

For more than a decade it has been known that certain growth factors inhibit apoptosis in genetically determined and experimental models of inner and outer retinal degeneration. The molecular mechanisms underlying these protective effects and the signaling that supports the survival of photoreceptors and retinal ganglion cells in these models have recently come under more in depth investigation. This paper reviews our current understanding of the balance of pro- and antiapoptotic signals that determine cell fate in the retina and how the activation of key signal transduction pathways by specific classes of neurotrophins protects retinal neurons.     

Bioreduction of platinum salts into nanoparticles: a mechanistic perspective

A mechanism for the bioreduction of H₂PtCl₆ and PtCl₂ into platinum nanoparticles by a hydrogenase enzyme from Fusarium oxysporum is proposed. Octahedral H₂PtCl₆ is too large to fit into the active region of the enzyme and, under conditions optimum for nanoparticle formation (pH 9, 65°C), undergoes a two-electron reduction to PtCl₂ on the molecular surface of the enzyme. This smaller molecule is transported through hydrophobic channels within the enzyme to the active region where, under conditions optimal for hydrogenase activity (pH 7.5, 38°C) it undergoes a second two-electron reduction to Pt(0). H₂PtCl₆ was unreactive at pH 7.5, 38°C; PtCl₂ was unreactive at pH 9, 65°C.     

The CBL–CIPK signaling module in plants: a mechanistic perspective

In a given environment, plants are constantly exposed to multitudes of stimuli. These stimuli are sensed and transduced to generate a diverse array of responses by several signal transduction pathways. Calcium (Ca²⁺) signaling is one such important pathway involved in transducing a large number of stimuli or signals in both animals and plants. Ca²⁺ engages a plethora of decoders to mediate signaling in plants. Among these groups of decoders, the sensor responder complex of calcineurin B‐like protein (CBL) and CBL‐interacting protein kinases (CIPKs) play a very significant role in transducing these signals. The signal transduction mechanism in most cases is phosphorylation events, but some structural role for the pair has also come to light recently. In this review, we discuss the structural nature of the sensor‐responder duo; their mechanism of substrate phosphorylation and also their structural role in modulating targets. Moreover, the mechanism of complex formation and mechanistic role of protein phosphatases with CBL–CIPK module has been mentioned. A comparison of CBL–CIPK with other decoders of Ca²⁺ signaling in plants also signifies the relatedness and diversity in signaling pathways. Further an attempt has been made to compare this aspect of Ca²⁺ signaling pathways in different plant species to develop a holistic understanding of conservation of stimulus–response‐coupling mediated by this Ca²⁺–CBL–CIPK module.     

The hippocampus and memory: a comparative and ethological perspective

During the past year, considerable progress has been made in our understanding of the wide-ranging functions of the hippocampus. Highlights include the development of new tasks with which to assess spatial/topographic memory in humans and monkeys, novel tests of relational memory in rats, and episodic-like memory tasks in birds. In addition, novel theories of hippocampal function have been developed that are notable for their applicability to both humans and animal models.     

In search of the vertebrate phylotypic stage: a molecular examination of the developmental hourglass model and von Baer's third law

In 1828, Karl von Baer proposed a set of four evolutionary "laws" pertaining to embryological development. According to von Baer's third law, young embryos from different species are relatively undifferentiated and resemble one another but as development proceeds, distinguishing features of the species begin to appear and embryos of different species progressively diverge from one another. An expansion of this law, called "the hourglass model," has been proposed independently by Denis Duboule and Rudolf Raff in the 1990s. According to the hourglass model, ontogeny is characterized by a starting point at which different taxa differ markedly from one another, followed by a stage of reduced intertaxonomic variability (the phylotypic stage), and ending in a von-Baer-like progressive divergence among the taxa. A possible "translation" of the hourglass model into molecular terminology would suggest that orthologs expressed in stages described by the tapered part of the hourglass should resemble one another more than orthologs expressed in the expansive parts that precede or succeed the phylotypic stage. We tested this hypothesis using 1,585 mouse genes expressed during 26 embryonic stages, and their human orthologs. Evolutionary divergence was estimated at different embryonic stages by calculating pairwise distances between corresponding orthologous proteins from mouse and human. Two independent datasets were used. One dataset contained genes that are expressed solely in a single developmental stage; the second was made of genes expressed at different developmental stages. In the second dataset the genes were classified according to their earliest stage of expression. We fitted second order polynomials to the two datasets. The two polynomials displayed minima as expected from the hourglass model. The molecular results suggest, albeit weakly, that a phylotypic stage (or period) indeed exists. Its temporal location, sometimes between the first-somites stage and the formation of the posterior neuropore, was in approximate agreement with the morphologically defined phylotypic stage. The molecular evidence for the later parts of the hourglass model, i.e., for von Baer's third law, was stronger than that for the earlier parts.     

Gamma-glutamyl transferases: A structural,mechanistic and physiological perspective

Gamma glutamyl transferases （GGT） are highly conserved enzymes that occur from bacteria to humans. They remove terminal y-glutamyl residue from peptides and amides. GGTs play an important role in the homeostasis of glutathione （a major cellular antioxidant） and in the detoxification of xenobiotics in mammals. They are implicated in diseases like diabetes, inflammation, neurodegenerative diseases and cardiovascular diseases. The physiological role of GGTs in bacteria is still unclear. Nothing is known about the basis for the strong conservation of the enzyme across the living system. The review focuses on the enzyme＇s physiology, chemistry and structural properties of the enzyme with emphasis on the evolutionary relationships. The available data indicate that the members of the GGT family share common structural features but are functionally heterogenous.     

Delineation of modular proteins: domain boundary prediction from sequence information

The delineation of domain boundaries of a given sequence in the absence of known 3D structures or detectable sequence homology to known domains benefits many areas in protein science, such as protein engineering, protein 3D structure determination and protein structure prediction. With the exponential growth of newly determined sequences, our ability to predict domain boundaries rapidly and accurately from sequence information alone is both essential and critical from the viewpoint of gene function annotation. Anyone attempting to predict domain boundaries for a single protein sequence is invariably confronted with a plethora of databases that contain boundary information available from the internet and a variety of methods for domain boundary prediction. How are these derived and how well do they work? What definition of 'domain' do they use? We will first clarify the different definitions of protein domains, and then describe the available public databases with domain boundary information. Finally, we will review existing domain boundary prediction methods and discuss their strengths and weaknesses.     

Evolutionary dynamics in the fungal polarization network,a mechanistic perspective

Polarity establishment underlies proper cell cycle completion across virtually all organisms. Much progress has been made in generating an understanding of the structural and functional components of this process, especially in model species. Here we focus on the evolutionary dynamics of the fungal polarization protein network in order to determine general components and mechanistic principles, species- or lineage-specific adaptations and the evolvability of the network. The currently available genomic and proteomic screens in a variety of fungal species have shown three main characteristics: (1) certain proteins, processes and functions are conserved throughout the fungal clade; (2) orthologous functions can never be assumed, as various cases have been observed of homologous loci with dissimilar functions; (3) species have, typically, various species- or lineage-specific proteins incorporated in their polarization network. Further large-scale comparative and experimental studies, including those on non-model species representing the great fungal diversity, are needed to gain a better understanding of the evolutionary dynamics and generalities of the polarization network in fungi.     

Fear memory and the amygdala: insights from a molecular perspective

The amygdala modulates memory consolidation and the storage of emotionally relevant information in other brain areas, and itself comprises a site of neural plasticity during aversive learning. These processes have been intensively studied in Pavlovian fear conditioning, a leading aversive learning paradigm that is dependent on the structural and functional integrity of the amygdala. The rapidness and persistence, and the relative ease, with which this conditioning paradigm can be applied to a great variety of species have made it an attractive model for neurochemical and electrophysiological investigations on memory formation. In this review we summarise recent studies which have begun to unravel cellular processes in the amygdala that are critical for the formation of long-term fear memory and have identified molecular factors and mechanisms of neural plasticity in this brain area.     

Determinants of excitability in cardiac myocytes: mechanistic investigation of memory effect

The excitability of a cardiac cell depends upon many factors, including the rate and duration of pacing. Furthermore, cell excitability and its variability underlie many electrophysiological phenomena in the heart. In this study, we used a detailed mathematical model of the ventricular myocyte to investigate the determinants of excitability and gain insight into the mechanism by which excitability depends on the rate and duration of pacing (the memory effect). Results: i) The primary determinant of excitability depends upon the duration (T) of the stimulus. ii) For a short T, excitability is determined by the difference between the threshold membrane potential and the resting membrane potential. iii) For a long T, excitability is determined by the resting membrane resistance, R(m). iv) In the case of long T, pacing induced changes in [Na(+)](i) and [Ca(2+)](i) over time affect R(m) and excitability by shifting the current-voltage (IV) curve in the vertical direction and are responsible for the memory effect. CONCLUSIONS: The results have important implications during an arrhythmia, where a cardiac cell may be subjected to rapid repetitive excitation for an extended period of time. Effective anti-arrhythmic strategies may be developed to exploit the R(m) dependence of excitability for a long T.     

The eye as a replicating and diverging, modular developmental unit

Sparked by new discoveries in developmental genetics, few topics have generated as much debate as eye evolution. This is somewhat surprising because the central controversy is not unique to eyes, but is a general theme of developmental genetics: evolutionarily conserved genes are deployed during the development of highly divergent morphological features. In the case of eyes, this paradox has engendered opposing camps entrenched in what has been termed a ‘scientific war’. One camp highlights conserved genetic features, concluding that eyes stem from an ancestral prototype. The opposing camp emphasizes variation, arguing that some eyes must have recruited the same genes after separate morphological origins. Here, I blur the line between these camps and suggest that eyes have often evolved by replication, perhaps through the ectopic expression of a conserved, modular regulatory cascade to produce serially homologous structures that often diverged during evolution. Therefore, morphologically diverse eyes could stem from a single ancestral prototype, yet also result from multiple morphological origins.     

Recognition memory and the medial temporal lobe: a new perspective

Recognition memory is widely viewed as consisting of two components, recollection and familiarity, which have been proposed to be dependent on the hippocampus and the adjacent perirhinal cortex, respectively. Here, we propose an alternative perspective: we suggest that the methods traditionally used to separate recollection from familiarity instead separate strong memories from weak memories. A review of work with humans, monkeys and rodents finds evidence for familiarity signals (as well as recollection signals) in the hippocampus and recollection signals (as well as familiarity signals) in the perirhinal cortex. We also indicate ways in which the functions of the medial temporal lobe structures are different, and suggest that these structures work together in a cooperative and complementary way.