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Leonard Zon, MD, & Catherine Limperopoulos, PhD
The cerebellum's unsung role in cognition and behavior
The cerebellum's unsung role in cognition and behavior
Cognitive functions, like language and visual processing, have long been thought to reside primarily in the brain's cerebrum. But researcher Catherine Limperopoulos, PhD, in Children's Hospital Boston's Department of Neurology, is documenting an important cognitive role for the cerebellum, previously thought to be chiefly involved in motor coordination. Her team is also finding that cerebellar injury is common in very low-birth-weight babies and can cause wide-ranging developmental problems.
In one study, published earlier this year, the researchers showed that the cerebellum grows rapidly in late gestation—much faster than the cerebral hemispheres’Äîand that premature birth arrests this growth. Another study compared two groups of toddlers born prematurely: 31 with cerebellar hemorrhage identified at birth (but no cerebral injury), and 31 controls whose brain scans were normal. In addition to motor problems, 61 percent of the children with cerebellar injury’Äîversus just 3 percent of controls’Äîhad global developmental delays, including deficits in language, visual reception and social/behavioral function.
Now, in the October Pediatrics, Limperopoulos and colleagues report that the cerebrum and cerebellum are tightly interconnected and modulate each other's growth and development. MRI imaging of 74 preterm infants showed that when the cerebrum was injured on one side, the opposite cerebellar hemisphere failed to reach normal size. Similarly, when one cerebellar hemisphere was injured, the opposite cerebral hemisphere was abnormally small.
Limperopoulos continues to follow children with cerebellar injury. "We want to understand what happens over time," she says. "The way the brain adapts and reorganizes after injury may be the best indicator of how a child will do."
Boosting production of blood-forming stem cells
Researchers led by Leonard Zon, MD, director of the Stem Cell/Developmental Biology Program at Children's Hospital Boston, and a Howard Hughes Medical Institute investigator, have discovered a possible way to increase production of blood-forming stem cells, also called hematopoietic stem cells (HSCs). Their findings, in the October issue of Genes and Development, could eventually help cancer patients and others who need HSCs for stem cell transplants.
Prior experiments hinted that a regulatory gene called Notch might play a role in HSC replication. Zon's team worked with a mutant strain of zebrafish that lacks Notch signaling and does not produce HSCs in adulthood. Through some clever genetics, they arranged for Notch signaling to be activated only in adult fish, by exposing them to a brief pulse of heat. (Activating Notch earlier would cause unwanted effects.) When given the pulse of heat, the fish began to produce more HSCs.
The researchers further found that Notch regulates HSC production by controlling another gene called runx1, and tested whether activating the Notch-Runx pathway could restore HSC production in zebrafish exposed to radiation. They exposed some of the irradiated fish to heat, activating Notch, and found that their blood counts recovered far more quickly.
"If we had a pharmaceutical compound to activate Notch transiently, it might restore the blood system more quickly in patients receiving stem cell transplants," speculates Zon.
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