TY - JOUR
T1 - Anti-osteogenic function of a LIM-homeodomain transcription factor LMX1B is essential to early patterning of the calvaria
AU - Cesario, Jeffry M.
AU - Landin Malt, André
AU - Chung, Jong Uk
AU - Khairallah, Michael P.
AU - Dasgupta, Krishnakali
AU - Asam, Kesava
AU - Deacon, Lindsay J.
AU - Choi, Veronica
AU - Almaidhan, Asma A.
AU - Darwiche, Nadine A.
AU - Kim, Jimin
AU - Johnson, Randy L.
AU - Jeong, Juhee
N1 - Funding Information:
We thank Dr. Jean-Pierre Saint-Jeannet and his laboratory members for helpful discussions and sharing equipment. We acknowledge Dr. Shoshana Yakar and Ripa Chowdhury of NYU College of Dentistry Micro-CT core for their help with the analysis. This work was supported by National Institutes of Health ( R03 DE023617 and R01 DE026798 to J.J.)
Publisher Copyright:
© 2018 Elsevier Inc.
PY - 2018/11/15
Y1 - 2018/11/15
N2 - The calvaria (upper part of the skull) is made of plates of bone and fibrous joints (sutures and fontanelles), and the proper balance and organization of these components are crucial to normal development of the calvaria. In a mouse embryo, the calvaria develops from a layer of head mesenchyme that surrounds the brain from shortly after mid-gestation. The mesenchyme just above the eye (supra-orbital mesenchyme, SOM) generates ossification centers for the bones, which then grow toward the apex gradually. In contrast, the mesenchyme apical to SOM (early migrating mesenchyme, EMM), including the area at the vertex, does not generate an ossification center. As a result, the dorsal midline of the head is occupied by sutures and fontanelles at birth. To date, the molecular basis for this regional difference in developmental programs is unknown. The current study provides vital insights into the genetic regulation of calvarial patterning. First, we showed that osteogenic signals were active in both EMM and SOM during normal development, which suggested the presence of an anti-osteogenic factor in EMM to counter the effect of these signals. Subsequently, we identified Lmx1b as an anti-osteogenic gene that was expressed in EMM but not in SOM. Furthermore, head mesenchyme-specific deletion of Lmx1b resulted in heterotopic ossification from EMM at the vertex, and craniosynostosis affecting multiple sutures. Conversely, forced expression of Lmx1b in SOM was sufficient to inhibit osteogenic specification. Therefore, we conclude that Lmx1b plays a key role as an anti-osteogenic factor in patterning the head mesenchyme into areas with different osteogenic competence. In turn, this patterning event is crucial to generating the proper organization of the bones and soft tissue joints of the calvaria.
AB - The calvaria (upper part of the skull) is made of plates of bone and fibrous joints (sutures and fontanelles), and the proper balance and organization of these components are crucial to normal development of the calvaria. In a mouse embryo, the calvaria develops from a layer of head mesenchyme that surrounds the brain from shortly after mid-gestation. The mesenchyme just above the eye (supra-orbital mesenchyme, SOM) generates ossification centers for the bones, which then grow toward the apex gradually. In contrast, the mesenchyme apical to SOM (early migrating mesenchyme, EMM), including the area at the vertex, does not generate an ossification center. As a result, the dorsal midline of the head is occupied by sutures and fontanelles at birth. To date, the molecular basis for this regional difference in developmental programs is unknown. The current study provides vital insights into the genetic regulation of calvarial patterning. First, we showed that osteogenic signals were active in both EMM and SOM during normal development, which suggested the presence of an anti-osteogenic factor in EMM to counter the effect of these signals. Subsequently, we identified Lmx1b as an anti-osteogenic gene that was expressed in EMM but not in SOM. Furthermore, head mesenchyme-specific deletion of Lmx1b resulted in heterotopic ossification from EMM at the vertex, and craniosynostosis affecting multiple sutures. Conversely, forced expression of Lmx1b in SOM was sufficient to inhibit osteogenic specification. Therefore, we conclude that Lmx1b plays a key role as an anti-osteogenic factor in patterning the head mesenchyme into areas with different osteogenic competence. In turn, this patterning event is crucial to generating the proper organization of the bones and soft tissue joints of the calvaria.
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U2 - 10.1016/j.ydbio.2018.05.022
DO - 10.1016/j.ydbio.2018.05.022
M3 - Article
C2 - 29852132
AN - SCOPUS:85047758170
SN - 0012-1606
VL - 443
SP - 103
EP - 116
JO - Developmental Biology
JF - Developmental Biology
IS - 2
ER -