Poster Presentation ANZSCDB National Scientific Meeting 2019

Angiocrine IGF-1 promotes Meckel’s cartilage proliferation to drive jaw growth during embryogenesis (#Poster 29)

Ceilidh Marchant 1 , Peter Anderson 2 , Quenten Schwarz 1 , Sophie Wiszniak 1
  1. Centre for Cancer Biology, Adelaide, SA, Australia
  2. Australian Craniofacial Unit, Adelaide, SA, Australia

Craniofacial development is a complex morphogenic process that relies on highly orchestrated interactions between multiple different cell types, including neural crest cells. A subset of neural crest cells that migrate into the mandibular primordia differentiate into chondrocytes which form Meckel’s cartilage, an arrowhead-shaped cartilage structure which serves as a scaffold for the mandible bone to ossify around.  We recently found [1] that proliferation of chondrocytes in Meckel’s cartilage during a critical developmental time-window is the driving force behind correct jaw outgrowth, and that vascular defects in the jaw correlate with craniofacial malformations in Wnt1-Cre; Vegfafl/flmice and in human patients. We further presented the novel concept that blood vessel-derived angiocrine factors are essential for mediating Meckel’s cartilage growth.

‘Angiocrine’ factors are secreted directly from the endothelial or mural cell components of blood vessel walls to instruct tissue morphogenesis.  To identify angiocrine factors that promote cartilage proliferation, phospho-RTK arrays were performed on chondrocytes treated with aortic-conditioned media to assay changes in signalling pathway activation. The IGF-1R was identified as a key candidate.  Treatment of primary Meckel’s cartilage chondrocytes with recombinant IGF-1 induces proliferation to a similar extent as treatment with aortic conditioned media, and expression analysis on tissue sections also shows that IGF-1 expression is enriched around the mandibular vessel.

To test the angiocrine requirement for IGF-1 in jaw development, we have conditionally removed IGF-1 from blood vessels in Cdh5-CreERT2; Igf-1fl/flembryos. Preliminary data shows that when Igf-1 knockout is induced at E11.5-E12.5, embryos exhibit craniofacial defects including a shorter frontonasal process and Meckel’s cartilage. We further show a significant reduction in proliferation of Meckel’s cartilage chondrocytes, underpinning the jaw growth defects. This demonstrates endothelial cells provide an essential source of IGF-1 for craniofacial cartilage growth, and is the first in vivo evidence for IGF-1 function as an angiocrine factor.

 

  1. [1] Wiszniak S, Mackenzie F, Anderson P, Kabbara S, Ruhrberg C, Schwarz Q. (2015) Neural crest cell-derived VEGF promotes embryonic jaw extension. Proceedings of the National Academy of Sciences USA (PNAS), 112:6086.