Twist1 contributes to cranial bone initiation and dermal condensation by maintaining wnt signaling responsiveness

Abstract

Background: Specification of cranial bone and dermal fibroblast progenitors in the supraorbital arch mesenchyme is Wnt/ b-catenin signaling-dependent. The mechanism underlying how these cells interpret instructive signaling cues and differentiate into these two lineages is unclear. Twist1 is a target of the Wnt/b-catenin signaling pathway and is expressed in cranial bone and dermal lineages. Results: Here, we show that onset of Twist1 expression in the mouse cranial mesenchyme is dependent on ectodermal Wnts and mesenchymal b-catenin activity. Conditional deletion of Twist1 in the supraorbital arch mesenchyme leads to cranial bone agenesis and hypoplastic dermis, as well as craniofacial malformation of eyes and palate. Twist1 is preferentially required for cranial bone lineage commitment by maintaining Wnt responsiveness. In the conditional absence of Twist1, the cranial dermis fails to condense and expand apically leading to extensive cranial dermal hypoplasia with few and undifferentiated hair follicles. Conclusions: Thus, Twist1, a target of canonical Wnt/b-catenin signaling, also functions to maintain Wnt responsiveness and is a key effector for cranial bone fate selection and dermal condensation. Developmental Dynamics 245:144-156, 2016. V C 2015 Wiley Periodicals, Inc.

Cerebral Vein Malformations Result from Loss of Twist1 Expression and BMP Signaling from Skull Progenitor Cells and Dura

“…In contrast to other conditional Twist1 mouse mutants (Goodnough et al, 2015), approximately one-third of Twist1 CK0/ − ;Sm-Cre neonates survived to adults. Strikingly, the coronal, sagittal, and lambdoid sutures were poorly developed and/or absent, large gaps of tissue persisted between the skull bones, and fusion was evident between the remaining frBone and parBone rudiments (Figure 5D).…”

“…Although Twist1 has been shown in mouse to regulate cranial suture and skull patterning (Goodnough et al, 2015; Ting et al, 2009), cerebral blood vessel development has not been examined. To explore the etiology of CV abnormalities in TWIST1 mutation-positive humans, we first asked if human CV development could be modeled in mouse.…”

A tale of two cities: The genetic mechanisms governing calvarial bone development

“…(Goodnough et al, , ; Hill et al, ). The deletion of Twist1 leads to smaller calvarial bones, increased fontanelle size, and ectopic chondrogenesis in the posterior calvarial bones, similar to β‐catenin mutants (Bildsoe et al, ; Goodnough et al, , ; Krawchuk et al, ; Loebel et al, ; Reinhold, Kapadia, Liao, & Naski, ). A second candidate mechanism is that β‐catenin deletion leads to stabilization of SOX9 protein, and higher SOX9 levels negatively regulate Runx2 transcription and bone formation in vivo (Akiyama et al, ; Eames, Sharpe, & Helms, ; Zhou et al, ).…”

“…Conditional mutants of well-known signaling pathways of endochondral bone development, such as BMP, FGF, and Wnts, demonstrate that they are required for development and morphogenesis of the skull bones, but they primarily function downstream of the inductive patterning event (reviewed in Bhatt et al, 1993;Fan et al, 2016). However, the Wnt signaling pathway and its effectors, such as TWIST1, are required for calvarial bone fate; thereby qualifying Wnts as a candidate osteo-inductive signal (Day, Guo, Garrett-Beal, & Yang, 2005;Goodnough et al, 2012Goodnough et al, , 2014Goodnough, Dinuoscio, & Atit, 2016;Hill, Später, Taketo, Birchmeier, & Hartmann, 2005;Tran et al, 2010).…”

Wnt/β‐catenin signaling in the mouse embryonic cranial mesenchyme is required to sustain the emerging differentiated meningeal layers

“…The En1Cre/+ ; R26R/+ ; β‐catenin fl/de l mutants have ectopic cartilage nodules in place of calvarial bone and dermis. To test the requirement of calvarial bone primordia for specification of meningeal progenitors, we analyzed Dermo1Cre/+ ; R26R/+ ; Twist1 fl/fl mutants, which lack calvarial osteoprogenitors and Twist1 throughout the CM (Goodnough, DiNuoscio, & Atit, ). At E12.5, we found comparable expression domains of FOXC1 expression in the controls and conditional Twist1 mutants, suggesting the calvarial bone primordia and Twist1 are not required to specify FOXC1 + meningeal progenitors (Supporting Information Figure S4).…”