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| Switching On Cell Types Early In Embryo Development |
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| SciMed - Biology | |||
| TS-Si News Service | |||
| Thursday, 14 August 2008 16:30 | |||
 {sidebar id=31}Cincinnati, OH, USA. Our
 nervous system consists of a centralized brain and nerve cord (the CNS), as well as a peripheral sensory system (the PNS). They are intricately linked up to detect stimuli, process information, and execute out complex behavior. The overall architecture is a marvel; it is also the first of our major structures to develop. One of the fundamental questions in
neuroscience is how the appropriate neurons form and connect correctly during development. Certain genes specify neuronal subtypes and their migration to appropriate locations along the developing body axis. Now researchers have discovered a central molecular switch that opens new avenues for studying the causes of birth conditions, defects and diseases such as human cancers. Hox and Senseless Antagonism Functions as a Molecular Switch to Regulate EGF Secretion in the Drosophila PNS. David Li-Kroeger, Lorraine M. Witt, H. Leighton Grimes, Tiffany A. Cook, and Brian Gebelein. Developmental Cell 15(2) 298-308.
Scientists determined the switch to be a main tuning mechanism in fruit fly embryos for instructing cells whether to form sensory nerves or blood cells in different parts of the body. The research team is from the Cincinnati Children's Hospital Medical Center. They published their findings in Developmental Cell.
 The genes under study are conserved between species through the course of evolution — all the way from Drosophilia fruit flies to vertebrates and humans. The molecular switch occurs when two central control genes, Hox and Senseless (Sens), compete for influence to regulate genetic signals that instruct cells to differentiate and begin tissue and/or blood formation.
Vertebrates contain 39 different Hox genes that participate in the developmental control of the limbs and other important systems: nervous, skeletal, gastrointestinal, urogenital, and blood. Mutations and/or mis-expression of Hox factors can cause malformations of the limbs, as well as leukemias and cancers.
 Brian Gebelein, Ph.D., is a researcher in the division of Developmental Biology at Cincinnati Children's Hospital Medical Center and corresponding author of the study. Dr. Gebelein's laboratory studies nervous system development and genes that specify
neuron subtypes, their formation and how they migrate to their appropriate locations in the developing body. Understanding the influence of Hox transcription factors in cell differentiation along the anterior and posterior axis of the Drosophilia melangaster fruit fly is an important focal point of this research.Although Hox genes have long been known to specify distinct cell types along the developing body axes of vertebrates and non-vertebrates, it hasn't been clear how they regulate downstream gene transcription to form specific cells or tissues.
 Gebelein says the competition between Hox and Sens appears to be complementary, creating a balance of instructional influence that results in normal development. In what the researchers called "an unexpected Hox transcriptional mechanism," they detected the permissive regulation of a secreted protein called EGF, or epidermal growth factor. EGF is a cell messenger protein that affects cell differentiation, growth and epidermal development. The research team noticed that Hox's permissive regulation of EGF led to cell specification when it interacted with the influence of Sens in the peripheral nervous system.
Looking forward, the researchers plan to deepen their understanding of how the balanced competition between Hox and Sens actually works, and what happens in the way of birth defects or disease when it becomes unbalanced should Sens or Hox exercise excessive dominance.
"We now have a central mechanism we can use as a tool to look for triggers in the genome that work with Hox and Sens to regulate the formation of neurons and blood cells," said Dr. Gebelein.
"This allows us to identify other key genes downstream of Hox and Sens, determine their role in development based on what happens with
cell fate decisions, and look for the causes of birth defects and disease."In collaboration with H. Leighton Grimes, Ph.D., of Cincinnati Children's division of Immunobiology, Dr. Gebelein is also studying how Hox competes with Sens and its control of a growth factor called Gfi-1.
In the current study, the researchers note that ongoing mouse studies at Cincinnati Children's show Gfi-1 and Hox are linked to neural and blood development. The researchers are looking into the implications this has for leukemia, said Dr. Gebelein, also an associate professor of pediatrics at the University of Cincinnati School of Medicine.
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