Date: 2009-11-12
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HOUSTON -- (November 12, 2009) -- Mice born lacking the gene Math1 – known to affect balance, hearing and the sense of physical self in relation to the world (proprioception) – die shortly after birth because they cannot breathe on their own.
(Media-Newswire.com) - HOUSTON -- (November 12, 2009) -- Mice born lacking the gene Math1 – known to affect balance, hearing and the sense of physical self in relation to the world (proprioception) – die shortly after birth because they cannot breathe on their own.
Why this occurred was a mystery until researchers from Baylor College of Medicine and the University of Alberta in Edmonton, Canada, teamed up to find that lack of the gene disrupts the differentiation and migration of a group of neurons that enable respiration right after birth. Without these neurons (the parafacial respiratory group/retrotrapezoid nucleus), the infant mice die. Mutations in a gene (PHOX2B) also critical for this group of neurons (known as pFRG/RTN) are responsible for a disorder called congenital central hypoventilation syndrome or Ondine's curse.
Disease in newborns
"This is a disease we see in our neonatal intensive care unit," said Dr. Kaashif A. Ahmad, a fellow in neonatology and in the laboratory of Dr. Huda Zoghbi, professor of pediatrics, neuroscience and molecular and human genetics at BCM and a Howard Hughes Medical Institute investigator. The lack of Math1 affects the development of these particular neurons as well as neurons near the pre-Bötzinger complex, another area critical to respiration. (Math1 was first identified in Zoghbi's laboratory in 1999.)
Although Math1 itself is not directly linked to any particular disease, Zoghbi pursued functional studies on Math1, convinced that understanding normal development through basic research often provides unparalleled medical insight.
Neurons critical for breathing
"The fact that Math1 controls the development of a number of neurons, some of which are critical for breathing, now opens up the possibility that some of the genes regulated by Math1 in these neurons are responsible for breathing abnormalities in newborns," said Zoghbi, who is also director of the Jan and Dan Duncan Neurological Research Institute at Texas Children's Hospital.
"The take-home message is that Math1 is not just required for the development of neurons critical for hearing or proprioception," said Ahmad, who is one of three first authors on the report. The other two include Dr. Matthew F. Rose also from Zoghbi's laboratory at BCM and Dr. Jun Ren of the University of Alberta. "These neurons are linked to the critical brainstem respiratory network by Math1."
Understanding other diseases
This finding could not only affect the understanding of congenital central hypoventilation syndrome, a fairly rare disorder, but opens new doors to understanding at least some cases of sudden infant death syndrome and other disorders linked to problems with breathing.
Because Math1 is an important link to a network of genes that control a variety of activities, understanding its effects may enable scientists and physicians to understand genes in that network that could have a direct effect on a particular disorder. The phenotype or observable signs of a genetic problem could give a clue as to whether genes in the Math1 network are involved, said Ahmad.
Math1 dependent networks
"It would be reasonable to investigate this if you have a human disorder with a breathing abnormalities and one of the other Math1 dependent networks – arousal, balance, hearing or proprioception – involved as well," he said.
These results have shown that Math1 is required for multiple components of the hindbrain respiratory network, some of which are involved in congenital respiratory disorders," said Rose. "Our task in future studies will be to identify precisely which of these neurons are most important in human disease and how we can treat them through approaches such as pharmacological intervention."
Others who took part in this work include Hsiao-Tuan Chao, Tiemo J. Klisch, Adriano Flora, all of BCM and Dr. John J. Greer of the University of Alberta (another senior author).
Greer notes that "data from this study reinforces the importance of the neurotransmitter glutamate for the generation of stable breathing and lends support for recent pharmacological interventions (drugs) to counter respiratory depression with Ampakines, a class of drugs that acts via glutamate receptors."
Funding for this work came from the National Institute of Neurological Diseases and Stroke, the National Institute of Mental Health, the National Institute of Child Health and Human Development, Baylor Research Advocates for Students Scientists, the Robert and Janice McNair Foundation, the Baylor Intellectual and Developmental Disabilities Core, the Alberta Heritage Foundation for Medical Research, Canadian Institutes for Health Research and the Howard Hughes Medical Institute.
The article is available at http://www.cell.com/neuron/.
For more information on basic science research at Baylor College of Medicine, please go to www.bcm.edu/fromthelab or www.bcm.edu/news.