Lrp4/Wise regulates palatal rugae development through Turing-type reaction-diffusion mechanisms

Abstract

Periodic patterning of iterative structures is diverse across the animal kingdom. Clarifying the molecular mechanisms involved in the formation of these structure helps to elucidate the process of organogenesis. Turing-type reaction-diffusion mechanisms have been shown to play a critical role in regulating periodic patterning in organogenesis. Palatal rugae are periodically patterned ridges situated on the hard palate of mammals. We have previously shown that the palatal rugae develop by a Turing-type reaction-diffusion mechanism, which is reliant upon Shh (as an inhibitor) and Fgf (as an activator) signaling for appropriate organization of these structures. The disturbance of Shh and Fgf signaling lead to disorganized palatal rugae. However, the mechanism itself is not fully understood. Here we found that Lrp4 (transmembrane protein) was expressed in a complementary pattern to Wise (a secreted BMP antagonist and Wnt modulator) expression in palatal rugae development, representing Lrp4 expression in developing rugae and Wise in the inter-rugal epithelium. Highly disorganized palatal rugae was observed in both Wise and Lrp4 mutant mice, and these mutants also showed the downregulation of Shh signaling, which was accompanied with upregulation of Fgf signaling. Wise and Lrp4 are thus likely to control palatal rugae development by regulating reaction-diffusion mechanisms through Shh and Fgf signaling. We also found that Bmp and Wnt signaling were partially involved in this mechanism.

Palatal rugae morphology is associated with variation in tooth number

“…These include WNT signalling, with ablation of signal in the oral epithelium preventing rugae formation 26 and BMP signalling 24 . Indeed, loss-of-function mutations in Sostdc1, which encodes a secreted BMP anatagonist and WNT modulator, results in a failure of fusion associated with anterior ruga 4 and disorganized rugae morphology in the mouse 25,38 . Although human rugae morphology is more complex than that in the mouse, the fundamental mechanisms are likely to be conserved at the molecular level 28 .…”

“…In recent years, a number of gene mutations have been identified in association with human forms of tooth agenesis, including MSX1 34 , PAX9 35 , WNT10A 36 and AXIN2 37 . Given that many of these genes and components within the associated signal pathways are also expressed in the rugae 23,24,38 , it can be hypothesised that variation in tooth number might be related to alterations in rugae pattern through disruption of common genetic pathways. There is some preliminary evidence for this, including findings of altered rugae patterns in families with sporadic hypodontia associated with variation in the interferon regulatory factor 6 (IRF6) gene 8 and individuals with variation in WNT3A and WNT11 39 .…”

Genetics and signaling mechanisms of orofacial clefts

“…Each new rugal domain is formed immediately anterior to ruga 8, which is formed first and corresponds with the boundary between anterior Shox2 and posterior Meox2 expression (Pantalacci et al, 2008). This expression pattern is regulated by a reaction‐diffusion mechanism involving antagonistic activities between Lrp4 and Sostdc1 , which are complementarily expressed in the prospective rugal and inter‐rugal domains, respectively (Kawasaki et al, 2018). Lrp4 and Sostdc1 may modulate Wnt signaling and Wnt is required to establish Shh signaling centers during rugae induction.…”

“…(C. Lin et al, 2011). When either of Lrp4 or Sostdc1 is knocked out, Shh expression domains become disordered, resulting in erratic ridge patterning (Kawasaki et al, 2018).…”

Wnt signaling in orofacial clefts: crosstalk, pathogenesis and models

“…Palatal rugae are established by Shh expression, which is opposed by Fgf signaling at the inter-rugal regions of the epithelium (Economou et al, 2012). Wnt/β-catenin signaling is also required for Shh induction in the palatal rugae (Lin et al, 2011; Kawasaki et al, 2018).…”