Abstract
Platelet-Derived Growth Factor Receptor ¿ (PDGFR¿) is a receptor tyrosine kinase crucial for the survival,
proliferation, differentiation and migration of mesenchymal cells in development. PDGF binding to PDGFR¿
induces receptor dimerization, which allows a conformational change in the kinase domain of the receptor and
autophosphorylation of tyrosine residues on the PDGFR¿ intracellular domain. Activating mutations in PDGFRB
have been recently discovered in humans. These activating mutations cause the receptor kinase domain to
remain in a constitutively active state even without ligand binding or receptor dimerization. Penttinen Syndrome
is an ultra-rare disease caused by a V665A point mutation in the kinase domain of PDGFR¿. Craniofacial
phenotypes appear during childhood including craniosynostosis, thin calvarium, Wormian bones, and midface
retrusion. Little is currently known regarding the full range of phenotypes associated with the V665A mutation.
Even less is known about how this excess of PDGFR¿ signaling leads to human disease. To address this gap
in knowledge, a mouse model with a conditional V665A mutation in the Pdgfrb gene has been generated.
Reminiscent of Penttinen Syndrome patients, V665A mice (V) exhibit craniofacial defects. Additionally,
preliminary studies show that signal transducer and activator of transcription 1 (STAT1) is overexpressed and
phosphorylated in cranial mesenchyme. It is hypothesized that constitutive PDGFR¿-V665A signaling through
STAT1 interferes with cranial development by inhibiting key transcription factors required for mesenchymal
progenitors to form meninges. First, this proposal will identify the cellular mechanisms of craniofacial defects in
V665A mutants (Aim 1) by assessing apoptosis, proliferation, differentiation, and migration of cranial
mesenchyme during embryo development, by investigating whether these processes are normalized by deletion
of STAT1, and using lineage-specific Cre mice to determine the cellular origin of the defects. Second, it will
identify molecular mechanisms (Aim 2) using bulk RNA sequencing and Cleavage Under Targets & Release
Using Nuclease (CUT&RUN) on cranial mesenchyme from control and PDGFR¿-V665A mutant embryos. These
studies will expand the current understanding of PDGFR¿ signaling and will illuminate how elevated signaling
leads to craniofacial defects in humans. Furthermore, the results of these studies may inform the adjacent fields
of cancer and cardiovascular disease as there is evidence of upregulated PDGF signaling in these diseases.