Anti-osteogenic function of a LIM-homeodomain transcription factor LMX1B is essential to early patterning of the calvaria

Jeffry M. Cesario, André Landin Malt, Jong Uk Chung, Michael P. Khairallah, Krishnakali Dasgupta, Kesava Asam, Lindsay J. Deacon, Veronica Choi, Asma A. Almaidhan, Nadine A. Darwiche, Jimin Kim, Randy L. Johnson, Juhee Jeong

Research output: Contribution to journalArticle

Abstract

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.

Original languageEnglish (US)
JournalDevelopmental Biology
DOIs
StateAccepted/In press - Jan 1 2018

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Mesoderm
Skull
Transcription Factors
Head
Sutures
Osteogenesis
Joints
Organizations
Bone Plates
Heterotopic Ossification
Bone and Bones
Craniosynostoses
Mental Competency

ASJC Scopus subject areas

  • Molecular Biology
  • Developmental Biology
  • Cell Biology

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Anti-osteogenic function of a LIM-homeodomain transcription factor LMX1B is essential to early patterning of the calvaria. / Cesario, Jeffry M.; Landin Malt, André; Chung, Jong Uk; Khairallah, Michael P.; Dasgupta, Krishnakali; Asam, Kesava; Deacon, Lindsay J.; Choi, Veronica; Almaidhan, Asma A.; Darwiche, Nadine A.; Kim, Jimin; Johnson, Randy L.; Jeong, Juhee.

In: Developmental Biology, 01.01.2018.

Research output: Contribution to journalArticle

Cesario, JM, Landin Malt, A, Chung, JU, Khairallah, MP, Dasgupta, K, Asam, K, Deacon, LJ, Choi, V, Almaidhan, AA, Darwiche, NA, Kim, J, Johnson, RL & Jeong, J 2018, 'Anti-osteogenic function of a LIM-homeodomain transcription factor LMX1B is essential to early patterning of the calvaria', Developmental Biology. https://doi.org/10.1016/j.ydbio.2018.05.022
Cesario, Jeffry M. ; Landin Malt, André ; Chung, Jong Uk ; Khairallah, Michael P. ; Dasgupta, Krishnakali ; Asam, Kesava ; Deacon, Lindsay J. ; Choi, Veronica ; Almaidhan, Asma A. ; Darwiche, Nadine A. ; Kim, Jimin ; Johnson, Randy L. ; Jeong, Juhee. / Anti-osteogenic function of a LIM-homeodomain transcription factor LMX1B is essential to early patterning of the calvaria. In: Developmental Biology. 2018.
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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

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