Pbx loss in cranial neural crest, unlike in epithelium, results in cleft palate only and a broader midface

• Ian C. Welsh ^[3] ; James Hart ^[1] ; Joel M. Brown ^[1] ; Karissa Hansen ^[3] ; Marcelo Rocha Marques ^[2] ; Robert J. Aho ^[3] ; Irina Grishina ^[4] ; Romulo Hurtado ^[1] ; Doris Herzlinger ^[1] ; Elisabetta Ferretti ^[5] ; Maria J. Garcia‐Garcia ^[1] ; Licia Selleri ^[6]
  1. [1] Cornell University

     Cornell University

     City of Ithaca, Estados Unidos

     
  2. [2] Institute of Human Genetics

     Institute of Human Genetics

     Poznań, Polonia

     
  3. [3] 1 Program in Craniofacial Biology Departments of Orofacial Sciences and Anatomy Institute of Human Genetics University of California San Francisco San Francisco CA USA
  4. [4] 2 Department of Cell and Developmental Biology Weill Cornell Medical College of Cornell University New York NY USA; 6Present address: Department of Urology New York University School of Medicine New York NY USA
  5. [5] 2 Department of Cell and Developmental Biology Weill Cornell Medical College of Cornell University New York NY USA; 7Present address: DanStem University of Copenhagen Bledamsvej 3B Copenhagen 2200 Denmark
  6. [6] 1 Program in Craniofacial Biology Departments of Orofacial Sciences and Anatomy Institute of Human Genetics University of California San Francisco San Francisco CA USA; 2 Department of Cell and Developmental Biology Weill Cornell Medical College of Cornell University New York NY USA

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• Localización: Journal of Anatomy, ISSN 0021-8782, Vol. 233, Nº. 2, 2018, págs. 222-242
• Idioma: inglés
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• Resumen

  • Orofacial clefting represents the most common craniofacial birth defect. Cleft lip with or without cleft palate (CL/P) is genetically distinct from cleft palate only (CPO). Numerous transcription factors (TFs) regulate normal development of the midface, comprising the premaxilla, maxilla and palatine bones, through control of basic cellular behaviors. Within the Pbx family of genes encoding Three Amino‐acid Loop Extension (TALE) homeodomain‐containing TFs, we previously established that in the mouse, Pbx1 plays a preeminent role in midfacial morphogenesis, and Pbx2 and Pbx3 execute collaborative functions in domains of coexpression. We also reported that Pbx1 loss from cephalic epithelial domains, on a Pbx2‐ or Pbx3‐deficient background, results in CL/P via disruption of a regulatory network that controls apoptosis at the seam of frontonasal and maxillary process fusion. Conversely, Pbx1 loss in cranial neural crest cell (CNCC)‐derived mesenchyme on a Pbx2‐deficient background results in CPO, a phenotype not yet characterized. In this study, we provide in‐depth analysis of PBX1 and PBX2 protein localization from early stages of midfacial morphogenesis throughout development of the secondary palate. We further establish CNCC‐specific roles of PBX TFs and describe the developmental abnormalities resulting from their loss in the murine embryonic secondary palate. Additionally, we compare and contrast the phenotypes arising from PBX1 loss in CNCC with those caused by its loss in the epithelium and show that CNCC‐specific Pbx1 deletion affects only later secondary palate morphogenesis. Moreover, CNCC mutants exhibit perturbed rostro‐caudal organization and broadening of the midfacial complex. Proliferation defects are pronounced in CNCC mutants at gestational day (E)12.5, suggesting altered proliferation of mutant palatal progenitor cells, consistent with roles of PBX factors in maintaining progenitor cell state. Although the craniofacial skeletal abnormalities in CNCC mutants do not result from overt patterning defects, osteogenesis is delayed, underscoring a critical role of PBX factors in CNCC morphogenesis and differentiation. Overall, the characterization of tissue‐specific Pbx loss‐of‐function mouse models with orofacial clefting establishes these strains as unique tools to further dissect the complexities of this congenital craniofacial malformation. This study closely links PBX TALE homeodomain proteins to the variation in maxillary shape and size that occurs in pathological settings and during evolution of midfacial morphology.