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Cleft lip with or without cleft palate (CL<\/jats:styled-content>\/P) is genetically distinct from cleft palate only (CPO<\/jats:styled-content>). Numerous transcription factors (TF<\/jats:styled-content>s) regulate normal development of the midface, comprising the premaxilla, maxilla and palatine bones, through control of basic cellular behaviors. Within the Pbx<\/jats:italic> family of genes encoding Three Amino\u2010acid Loop Extension (TALE<\/jats:styled-content>) homeodomain\u2010containing TF<\/jats:styled-content>s, we previously established that in the mouse, Pbx1<\/jats:italic> plays a preeminent role in midfacial morphogenesis, and Pbx2<\/jats:italic> and Pbx3<\/jats:italic> execute collaborative functions in domains of coexpression. We also reported that Pbx1<\/jats:italic> loss from cephalic epithelial domains, on a Pbx2<\/jats:italic>\u2010 or Pbx3<\/jats:italic>\u2010deficient background, results in CL<\/jats:styled-content>\/P via disruption of a regulatory network that controls apoptosis at the seam of frontonasal and maxillary process fusion. Conversely, Pbx1<\/jats:italic> loss in cranial neural crest cell (CNCC<\/jats:styled-content>)\u2010derived mesenchyme on a Pbx2<\/jats:italic>\u2010deficient background results in CPO<\/jats:styled-content>, a phenotype not yet characterized. In this study, we provide in\u2010depth analysis of PBX<\/jats:styled-content>1 and PBX<\/jats:styled-content>2 protein localization from early stages of midfacial morphogenesis throughout development of the secondary palate. We further establish CNCC<\/jats:styled-content>\u2010specific roles of PBX TF<\/jats:styled-content>s and describe the developmental abnormalities resulting from their loss in the murine embryonic secondary palate. Additionally, we compare and contrast the phenotypes arising from PBX<\/jats:styled-content>1 loss in CNCC<\/jats:styled-content> with those caused by its loss in the epithelium and show that CNCC<\/jats:styled-content>\u2010specific Pbx1<\/jats:italic> deletion affects only later secondary palate morphogenesis. Moreover, <\/jats:italic>CNCC<\/jats:styled-content> mutants exhibit perturbed rostro\u2010caudal organization and broadening of the midfacial complex. Proliferation defects are pronounced in CNCC<\/jats:styled-content> mutants at gestational day (E)12.5, suggesting altered proliferation of mutant palatal progenitor cells, consistent with roles of PBX<\/jats:styled-content> factors in maintaining progenitor cell state. Although the craniofacial skeletal abnormalities in CNCC<\/jats:styled-content> mutants do not result from overt patterning defects, osteogenesis is delayed, underscoring a critical role of PBX<\/jats:styled-content> factors in CNCC<\/jats:styled-content> morphogenesis and differentiation. Overall, the characterization of tissue\u2010specific Pbx<\/jats:italic> loss\u2010of\u2010function 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<\/jats:styled-content> homeodomain proteins to the variation in maxillary shape and size that occurs in pathological settings and during evolution of midfacial morphology.<\/jats:p>","DOI":"10.1111\/joa.12821","type":"journal-article","created":{"date-parts":[[2018,5,24]],"date-time":"2018-05-24T00:17:11Z","timestamp":1527121031000},"page":"222-242","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":28,"title":["Pbx loss in cranial neural crest, unlike in epithelium, results in cleft palate only and a broader midface"],"prefix":"10.1111","volume":"233","author":[{"given":"Ian C.","family":"Welsh","sequence":"first","affiliation":[{"name":"Program in Craniofacial Biology Departments of Orofacial Sciences and Anatomy Institute of Human Genetics University of California San Francisco San Francisco CA 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