Newly Discovered Molecular Switch Helps Decide Cell Type in Early Embryo Development

Finding at Cincinnati Children’s Creates New Path for Studying Birth Defects and Cancer

Tuesday, August 12, 2008

Researchers have discovered a central molecular switch in fruit fly embryos that opens new avenues for studying the causes of birth defects and cancer in humans. Writing about their study in the Aug. 12 Developmental Cell, scientists at Cincinnati Children’s Hospital Medical Center determined the switch to be a main tuning mechanism for instructing cells whether to form sensory nerves or blood cells in different parts of the body.

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, said Brian Gebelein, PhD, a researcher in the division of Developmental Biology at Cincinnati Children’s and corresponding author of the study.

Conserved between species through the course of evolution – all the way from Drosophila fruit flies to vertebrates and humans – Hox genes are responsible for regulating other downstream genes, to determine body position and help form major body structures during early development. Sens regulates downstream genes that support the development of sensory organs, such as those important to hearing, touch or site.

Dr. Gebelein said the competition between Hox and Sens appears to be complementary, creating a balance of instructional influence that results in normal development. Looking forward the researchers plan to deepen their understanding of how this balance 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.”

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. 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.

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 Drosophila melanogaster fruit fly is an important focal point of this research.

In collaboration with H. Leighton Grimes, PhD, 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.

Other researchers participating in the study included lead author, David Li-Kroeger, Lorraine M. Witt, Dr. Grimes and Tiffany A. Cook, all of Cincinnati Children’s. Funding support came from an MOD Basil O’Connor Award, an ACS Ohio Pilot Grant, a grant from the Barrett Cancer Center at the University of Cincinnati and the National Institutes of Health.

Cincinnati Children's Hospital Medical Center is one of America’s top three children’s hospitals for general pediatrics and is highly ranked for its expertise in digestive diseases, respiratory diseases, cancer, neonatal care, heart care and neurosurgery, according to the annual ranking of best children's hospitals by U.S. News & World Report. One of the three largest children’s hospitals in the U.S., Cincinnati Children’s is affiliated with the University of Cincinnati College of Medicine and is one of the top two recipients of pediatric research grants from the National Institutes of Health. For its achievements in transforming healthcare, Cincinnati Children's is one of six U.S. hospitals since 2002 to be awarded the American Hospital Association-McKesson Quest for Quality Prize ® for leadership and innovation in quality, safety and commitment to patient care. The hospital is a national and international referral center for complex cases, so that children with the most difficult-to-treat diseases and conditions receive the most advanced care leading to better outcomes.