September 16, 2013
In the late 1980s, a team of scientists wanted to know how cells born of the same precursor, or mother, cell know biochemically to opt in and “acquire the identity of” a neuron instead of, say, a glial cell. Or vice versa. So they began systematically inactivating individual genes one by one in embryonic fruit flies (Drosophila melanogaster
). The hope was one of the silenced genes would produce flies with poorly differentiated sensory cells and lead them in the right direction to explore the issue in greater biochemical detail.
They soon got their informative gene and, in keeping with the freewheeling laboratory culture of fruit fly geneticists, gave it the whimsical name of numb. Why numb? Mutations in the gene caused developing fruit flies to lack about 90 percent of their sensory neurons and appear to be, well, numb. Over the next decade, research groups around the world determined the numb gene and its many alternatively-spliced protein products, or isoforms, also play fundamental roles in establishing cell identity in tissues throughout most of the body.
Missing from the list were any of the tissues that comprise the tooth. That changed in 2007 when NIDCR-supported researchers detected in rodent studies that NUMB is differentially expressed in dentin-forming odontoblasts. Now, as published online in BioMed Research International
, the scientists and their colleagues have followed up to publish the first broad characterization of NUMB and its fundament role in tooth development.
The researchers determined in mouse studies that NUMB expression is time variable. In the developing tooth germ, for instance, no NUMB protein was detectable. But in the post-natal tooth germ, the scientists found NUMB was strongly and differentially expressed in the cervical loop, the stem-cell niche from which enamel forms, and in three cell types known to help form dental tissues. The cells include preameloblasts (undifferentiated enamel forming cells), odontoblasts, and dental pulp stem cells. In total, the researchers identified four likely NUMB isoforms.
Because of the temporal and spatial differences in NUMB expression, the researchers wondered whether the protein might play a specific regulatory role during post-natal tooth development. If so, deciphering it would be important not only to better understand the biology of a tooth but also as a potentially exploitable regulatory factor to one day learn to better engineer replacement tooth tissue.
To get their answer, the scientists turned their attention to a preameloblast cell line called HAT-7. The researchers reasoned that NUMB might interact in the preameloblast with the protein Notch1, which previous studies suggest plays a role in specifying dental cell-type identity. Their hunch proved correct. As NUMB expression increases, Notch1 levels decrease dramatically and result in reduced downstream signaling events. The scientists proposed that, by turning down NUMB and its downstream partners, NUMB maintains a preamleoblast cell identity in the cervical loop that can be influenced to differentiate into ameloblasts and form new enamel.
The paper is titled Expression and Function of NUMB in Odontogenesis. It was published online in June in the journal BioMed Research International
. The authors are Haitao Li, Amsaveni Ramachadran, Qi Gao, Sriram Ravindran, Yiqiang Song, Carla Evans, and Anne George.