Brachydactyly is a condition characterized by shortening of the fingers and toes. Loss of a key protein leads to defects in skeletal development
including reduced bone density and brachydactyly, discovered researchers at Penn State University who knocked out the Speckle-type
POZ Protein (Spop) in the mouse and characterized the impact on bone
The research, which appears online in the journal Proceedings of the National Academy of Sciences
, redefines the role of Spop during bone development
and provides a new potential target for the diagnosis and treatment of
bone diseases such as osteoporosis.
‘The speckle-type POZ Protein (Spop) plays an important role during bone development and provides a new potential target for the diagnosis and treatment of bone diseases such as osteoporosis.’
"The Spop protein is involved in Hedgehog signaling - a
well-studied cell-to-cell communication pathway that plays multiple
roles during development," said Aimin Liu, associate professor of
biology at Penn State and the corresponding author of the study.
"Previous studies done in cell culture suggested that Spop negatively
regulates or 'turns down' Hedgehog signaling. However, in our study, we
show that Spop positively regulates the pathway downstream of a member
of the Hedgehog family, a protein called Indian Hedgehog, during bone
development. This new understanding adds to our knowledge of the genetic
basis of bone development and could open new avenues to study bone
Indian Hedgehog (Ihh) plays an essential role in bone development.
It is near the top of a hierarchical cascade of genes that program cells
to produce cartilage and bone. Ihh controls gene expression by
regulating the activity of the transcription factors - proteins that
control the expression of other genes - Gli2 and Gli3. Gli2 acts mainly
as an activator of gene expression and Gli3 acts mainly to repress gene
expression. The Spop protein tags the Gli proteins to be degraded in
"Previous studies led to a hypothesis that a loss of Spop function
would increase Hedgehog signaling because the Gli activators were no
longer being degraded," said Hongchen Cai, a graduate student at Penn
State and an author of the paper. "We were surprised to see in our study
the repressor of gene expression, Gli3, built up in developing bone,
but not the activator of gene expression, Gli2. This imbalance led to an
overall decrease in Hedgehog signaling."
In order to study the role of Spop in bone development more closely,
the researchers knocked the gene out specifically in the limb. Limbs
that lacked Spop had less dense bone, mimicking osteopenia - a human
condition characterized by low bone density, but not as severe as
osteoporosis. The limbs also had shorter than normal fingers and toes.
The researchers also showed that the effects of losing Spop could be
mitigated by simultaneously reducing the amount of Gli3 in the limbs.