PROJECT SUMMARY/ABSTRACT
Tissues in a developing (or regenerating) appendage must correctly interpret their location in biological space,
and use this positional information to inform size, pattern and shape during outgrowth. Relative changes in how
cells interpret their positions during development can lead to debilitating changes in appendage phenotype,
including limb malformations. Further, the ability to regenerate requires that tissues remember or reinterpret
positional identity, then re-deploy this information to guide regrowth. Nonetheless, despite incredible relevance
to both basic biology and biomedicine, it remains poorly understood how spatial context regulates the local
morphogenetic processes which sculpt the pattern and shape of growing organs. Understanding the nature of
positional identity in vertebrate appendages can further efforts to prevent, diagnose and treat congenital limb
disorders, and will be necessary for development of advanced regenerative therapies.
Zebra¿sh ¿ns are a powerful system for studying mechanisms of growth and regeneration, and the caudal (tail)
¿n possesses an elegant, simple-yet-informative structure. After amputation or removal of any portion of the
organ, ¿ns regenerate rapidly to reproduce the original size, patterning and shape. Long- and short-¿nned mu-
tants have served as crucial tools in decades of important progress towards the mechanisms regulating rela-
tive ¿n size. Fin length phenotypes preserve the proportional patterning and overall shape of the ¿n structure—
length is the only aspect of morphology that is altered. Indeed, before now, there have not been experimental
models to disrupt ¿n ray patterning or the forked shape of the ¿n, and this lack of experimental tools means
that essentially nothing is known about how pattern and shape are established or remembered.
In this proposal, researchers introduce novel phenotypes in which patterning and shape are decoupled from
size in the ¿n; these tools will be used to identify pathways and cellular processes underlying positional identity
and the morphogenesis of form. The team will initially focus on mechanisms of skeletal patterning along the
proximo-distal axis of ¿n rays, using the discovery that thyroid hormone regulates relative ray polarity. The re-
searchers next ask how identity is imprinted across the medio-lateral axis. The team has developed a system
in which the adult ¿n never develops a central cleft, and grows into a triangular rather than a forked shape.
This phenotype will be used to test a model in which larval Shh expression regulates relative morphogenetic
behaviors across the ¿n fold to pre-pattern the eventual forked shape of the organ. Researchers will explicitly
identify the cell states that constitute modules of positional identity regulating size, patterning and shape—the
three essential characteristics of overall ¿n morphology. In all, the proposed research will open fresh horizons
for the broader ¿eld, leveraging new paradigms by which different aspects of positional identity can inform
morphogenesis. These advances are expected to contribute foundational knowledge relevant in developing
clinical interventions for congenital disorders, and critical in laying the groundwork for regenerative medicine.
