Only accessible information is useful: insights from gradient-mediated patterning

Information theory is gaining popularity as a tool to characterize performance of biological systems. However, information is commonly quantified without reference to whether or how a system could extract and use it; as a result, information-theoretic quantities are easily misinterpreted. Here, we take the example of pattern-forming developmental systems which are commonly structured as cascades of sequential gene expression steps. Such a multi-tiered structure appears to constitute sub-optimal use of the positional information provided by the input morphogen because noise is added at each tier. However, one must distinguish between the total information in a morphogen and information that can be usefully extracted and interpreted by downstream elements. We demonstrate that quantifying the information that is accessible to the system naturally explains the prevalence of multi-tiered network architectures as a consequence of the noise inherent to the control of gene expression. We support our argument with empirical observations from patterning along the major body axis of the fruit fly embryo. We use this example to highlight the limitations of the standard information-theoretic characterization of biological signalling, which are frequently de-emphasized, and illustrate how they can be resolved

The Formation of the Bicoid Morphogen Gradient Requires Protein Movement from Anteriorly Localized mRNA

New quantitative data show that the Bicoid morphogen gradient is generated from a dynamic localized source and that protein gradient formation requires protein movement along the anterior-posterior axis

The Role of Glypicans in Wnt Inhibitory Factor-1 Activity and the Structural Basis of Wif1's Effects on Wnt and Hedgehog Signaling

Proper assignment of cellular fates relies on correct interpretation of Wnt and Hedgehog (Hh) signals. Members of the Wnt Inhibitory Factor-1 (WIF1) family are secreted modulators of these extracellular signaling pathways. Vertebrate WIF1 binds Wnts and inhibits their signaling, but its Drosophila melanogaster ortholog Shifted (Shf) binds Hh and extends the range of Hh activity in the developing D. melanogaster wing. Shf activity is thought to depend on reinforcing interactions between Hh and glypican HSPGs. Using zebrafish embryos and the heterologous system provided by D. melanogaster wing, we report on the contribution of glypican HSPGs to the Wnt-inhibiting activity of zebrafish Wif1 and on the protein domains responsible for the differences in Wif1 and Shf specificity. We show that Wif1 strengthens interactions between Wnt and glypicans, modulating the biphasic action of glypicans towards Wnt inhibition; conversely, glypicans and the glypican-binding “EGF-like” domains of Wif1 are required for Wif1's full Wnt-inhibiting activity. Chimeric constructs between Wif1 and Shf were used to investigate their specificities for Wnt and Hh signaling. Full Wnt inhibition required the “WIF” domain of Wif1, and the HSPG-binding EGF-like domains of either Wif1 or Shf. Full promotion of Hh signaling requires both the EGF-like domains of Shf and the WIF domains of either Wif1 or Shf. That the Wif1 WIF domain can increase the Hh promoting activity of Shf's EGF domains suggests it is capable of interacting with Hh. In fact, full-length Wif1 affected distribution and signaling of Hh in D. melanogaster, albeit weakly, suggesting a possible role for Wif1 as a modulator of vertebrate Hh signaling

Finishing the euchromatic sequence of the human genome

The sequence of the human genome encodes the genetic instructions for human physiology, as well as rich information about human evolution. In 2001, the International Human Genome Sequencing Consortium reported a draft sequence of the euchromatic portion of the human genome. Since then, the international collaboration has worked to convert this draft into a genome sequence with high accuracy and nearly complete coverage. Here, we report the result of this finishing process. The current genome sequence (Build 35) contains 2.85 billion nucleotides interrupted by only 341 gaps. It covers ∼99% of the euchromatic genome and is accurate to an error rate of ∼1 event per 100,000 bases. Many of the remaining euchromatic gaps are associated with segmental duplications and will require focused work with new methods. The near-complete sequence, the first for a vertebrate, greatly improves the precision of biological analyses of the human genome including studies of gene number, birth and death. Notably, the human enome seems to encode only 20,000-25,000 protein-coding genes. The genome sequence reported here should serve as a firm foundation for biomedical research in the decades ahead

The emergence of embryonic dorsal -ventral pattern through the interactions of BMP ligands with their receptors and modulators

Among all bilaterally symmetric animals so far examined, signaling by the family of Bone Morphogenetic Proteins (BMPs) patterns the embryonic dorsal-ventral (DV) axis. Proper DV patterning relies upon the formation of BMP signaling gradients which arise through the combined activities of a network of extracellular modulators regulating ligand-receptor interactions. In Drosophila, genetic analyses have revealed the contributions of two different classes of BMP type I receptors in propagating signaling from two BMP ligands, and uncovered the role of the evolutionarily conserved secreted factor Twisted gastrulation (Tsg) in modulating BMP signaling. However, in vertebrate embryos, several fundamental, related questions have not been addressed. Through a combination of genetics, overexpression, loss of function, and biochemistry, I examined the activities of Tsg and the BMP type I receptors in the zebrafish embryo, and explored the contributions of dimeric BMP ligands to DV patterning. Previously, overexpression analyses showed that Tsg could either promote or antagonize BMP signaling, depending on the presence of additional extracellular modulators Chordin and Tolloid. This left open the question of which of these roles predominates in the embryo. Using morpholino-based knockdown, I determined that Tsg promotes BMP signaling, cooperating with Tolloid, and acting at least in part independently of the presence of Chordin. Zebrafish embryos express five genes encoding type I BMP receptors. Of these, Alk8 is indispensible for DV patterning, but of the four related BMP type I receptors of the Alk3/6 class, no mutations have been described, and no loss of function study has implicated Alk3/6 in fish DV patterning. By combining analysis of a novel antimorphic alk3a mutant with morpholino-mediated loss of function, I find that these four genes perform overlapping functions during DV patterning, but that the divergent type I receptor Alk8 plays a nonredundant role. I show that only BMP heterodimers are capable of activating signaling in the embryo, and that they function by assembling receptor complexes containing both Alk3/6 and Alk8 polypeptides. I propose that only heterodimers possess sufficient receptor affinity to induce signaling in the presence of extracellular antagonists expressed during DV patterning

The emergence of embryonic dorsal -ventral pattern through the interactions of BMP ligands with their receptors and modulators

Among all bilaterally symmetric animals so far examined, signaling by the family of Bone Morphogenetic Proteins (BMPs) patterns the embryonic dorsal-ventral (DV) axis. Proper DV patterning relies upon the formation of BMP signaling gradients which arise through the combined activities of a network of extracellular modulators regulating ligand-receptor interactions. In Drosophila, genetic analyses have revealed the contributions of two different classes of BMP type I receptors in propagating signaling from two BMP ligands, and uncovered the role of the evolutionarily conserved secreted factor Twisted gastrulation (Tsg) in modulating BMP signaling. However, in vertebrate embryos, several fundamental, related questions have not been addressed. Through a combination of genetics, overexpression, loss of function, and biochemistry, I examined the activities of Tsg and the BMP type I receptors in the zebrafish embryo, and explored the contributions of dimeric BMP ligands to DV patterning. Previously, overexpression analyses showed that Tsg could either promote or antagonize BMP signaling, depending on the presence of additional extracellular modulators Chordin and Tolloid. This left open the question of which of these roles predominates in the embryo. Using morpholino-based knockdown, I determined that Tsg promotes BMP signaling, cooperating with Tolloid, and acting at least in part independently of the presence of Chordin. Zebrafish embryos express five genes encoding type I BMP receptors. Of these, Alk8 is indispensible for DV patterning, but of the four related BMP type I receptors of the Alk3/6 class, no mutations have been described, and no loss of function study has implicated Alk3/6 in fish DV patterning. By combining analysis of a novel antimorphic alk3a mutant with morpholino-mediated loss of function, I find that these four genes perform overlapping functions during DV patterning, but that the divergent type I receptor Alk8 plays a nonredundant role. I show that only BMP heterodimers are capable of activating signaling in the embryo, and that they function by assembling receptor complexes containing both Alk3/6 and Alk8 polypeptides. I propose that only heterodimers possess sufficient receptor affinity to induce signaling in the presence of extracellular antagonists expressed during DV patterning

Data from: Only accessible information is useful: insights from gradient-mediated patterning

Information theory is gaining popularity as a tool to characterise performance of biological systems. However, information is commonly quantified without reference to whether or how a system could extract and use it; as a result, information-theoretic quantities are easily misinterpreted. Here we take the example of pattern-forming developmental systems which are commonly structured as cascades of sequential gene expression steps. Such a multi-tiered structure appears to constitute sub-optimal use of the positional information provided by the input morphogen because noise is added at each tier. However, one must distinguish between the total information in a morphogen and information that can be usefully extracted and interpreted by downstream elements. We demonstrate that quantifying the information that is accessible to the system naturally explains the prevalence of multi-tiered network architectures as a consequence of the noise inherent to the control of gene expression. We support our argument with empirical observations from patterning along the major body axis of the fruit fly embryo. We use this example to highlight the limitations of the standard information-theoretic characterisation of biological signaling, which are frequently de-emphasized, and illustrate how they can be resolved