Evolution of Dosage Compensation
Organisms that utilize chromosome-based mechanisms to determine sex (e.g. XX, females and XY/XO, males) require the chromosome-wide regulatory mechanism of dosage compensation to balance sex-chromosome gene expression between sexes. Strategies to determine sexual fate and to compensate X-chromosome dosage between sexes have evolved independently: mammals, flies, and worms use fundamentally different methods. Therefore, understanding the evolution of dosage compensation requires comparisons over shorter evolutionary time-scales, such as between various nematode species. Understanding the molecular evolution of dosage compensation components and regulatory sequences will provide insights into mechanisms that control sex-specific chromosome-wide gene regulation, and how these mechanisms could facilitate novel functions, X-chromosome evolution, and promote biodiversity.
Comparative studies have illuminated remarkable variability in the conservation of developmental mechanisms. Nematode dosage compensation is a complex process that can be simplified into three distinct parts, the core machinery (the dosage compensation complex), the genetic hierarchy (genes, xol-1 and sdc-2) that regulates dosage compensation, and finally the DNA sequence requirements on the X chromosome. At the start of my post-doc it was of great interest to know how these “three distinct parts” evolved; whether they were all conserved, all diverged, or a combination of the two. This was a relatively unexplored aspect of nematode dosage compensation at the time.
Signaling Specificity Mediated by the C. elegans FGF Receptor Tyrosine Kinase
Fibroblast growth factors (FGFs) are responsible for initiating many different types of biological events, including cell proliferation, angiogenesis, differentiation, cell migration, and cell survival. The action of FGFs is mediated by FGFRs, a subfamily of receptor tyrosine kinases (RTKs). FGF binding causes FGFR dimerization, stimulating the activity of their intracellular tyrosine kinase domain, and triggering downstream events mediated by tyrosine autophosphorylation and the phosphorylation of other substrates.
Signaling specificity can be conferred by any of a variety of different mechanisms. Some aspects of signaling specificity derive from the status of the cells in which the event is happening: the specific panoply of transcription factors and signal transduction components available in a particular cell helps determine the specific response that is triggered. A second determinant of specificity derives from the spectrum of external stimuli that act in concert with the specific signal being studied. For example, cells within organisms are bathed in external stimuli, which include the nature of the extracellular substrates and adjacent cells they contact and the intercellular signals that surround them. In fact, the nature of the interaction between specific ligands and HSPGs is important for signaling specificity. A third mechanism that stimulates specific responses results from the use of structurally distinct receptor isoforms that modify the components of the signaling complex. In fact, evolution has led the family of RTKs to utilize various permutations of these mechanisms to effect the vast array of specific signaling events that they promote. Our studies use C. elegans as a model to understand FGF signaling specificity. The main goal is to understand how the activation of EGL-15, the sole worm FGFR, can trigger different biological responses, specifically focusing on two of those processes:
(1) the chemoattraction of the two myoblast precursors of the egg-laying muscles (sex myoblasts, SMs)
(2) the regulation of the balance of fluid within the organism (fluid homeostasis)
Organisms that utilize chromosome-based mechanisms to determine sex (e.g. XX, females and XY/XO, males) require the chromosome-wide regulatory mechanism of dosage compensation to balance sex-chromosome gene expression between sexes. Strategies to determine sexual fate and to compensate X-chromosome dosage between sexes have evolved independently: mammals, flies, and worms use fundamentally different methods. Therefore, understanding the evolution of dosage compensation requires comparisons over shorter evolutionary time-scales, such as between various nematode species. Understanding the molecular evolution of dosage compensation components and regulatory sequences will provide insights into mechanisms that control sex-specific chromosome-wide gene regulation, and how these mechanisms could facilitate novel functions, X-chromosome evolution, and promote biodiversity.
Comparative studies have illuminated remarkable variability in the conservation of developmental mechanisms. Nematode dosage compensation is a complex process that can be simplified into three distinct parts, the core machinery (the dosage compensation complex), the genetic hierarchy (genes, xol-1 and sdc-2) that regulates dosage compensation, and finally the DNA sequence requirements on the X chromosome. At the start of my post-doc it was of great interest to know how these “three distinct parts” evolved; whether they were all conserved, all diverged, or a combination of the two. This was a relatively unexplored aspect of nematode dosage compensation at the time.
Signaling Specificity Mediated by the C. elegans FGF Receptor Tyrosine Kinase
Fibroblast growth factors (FGFs) are responsible for initiating many different types of biological events, including cell proliferation, angiogenesis, differentiation, cell migration, and cell survival. The action of FGFs is mediated by FGFRs, a subfamily of receptor tyrosine kinases (RTKs). FGF binding causes FGFR dimerization, stimulating the activity of their intracellular tyrosine kinase domain, and triggering downstream events mediated by tyrosine autophosphorylation and the phosphorylation of other substrates.
Signaling specificity can be conferred by any of a variety of different mechanisms. Some aspects of signaling specificity derive from the status of the cells in which the event is happening: the specific panoply of transcription factors and signal transduction components available in a particular cell helps determine the specific response that is triggered. A second determinant of specificity derives from the spectrum of external stimuli that act in concert with the specific signal being studied. For example, cells within organisms are bathed in external stimuli, which include the nature of the extracellular substrates and adjacent cells they contact and the intercellular signals that surround them. In fact, the nature of the interaction between specific ligands and HSPGs is important for signaling specificity. A third mechanism that stimulates specific responses results from the use of structurally distinct receptor isoforms that modify the components of the signaling complex. In fact, evolution has led the family of RTKs to utilize various permutations of these mechanisms to effect the vast array of specific signaling events that they promote. Our studies use C. elegans as a model to understand FGF signaling specificity. The main goal is to understand how the activation of EGL-15, the sole worm FGFR, can trigger different biological responses, specifically focusing on two of those processes:
(1) the chemoattraction of the two myoblast precursors of the egg-laying muscles (sex myoblasts, SMs)
(2) the regulation of the balance of fluid within the organism (fluid homeostasis)