Bult, Carol

Hansen, Karissa

Hu, Diane

Losa-Llabata, Marta

Marcucio, Ralph

Mohun, Timothy

Osterwalder, Marco

Selleri, Licia

Swigut, Tomek

Visel, Axel

Wells, Julie

Welsh, Ian

Craniofacial morphogenesis demands coordinated outgrowth of spatially‐separated facial prominences. Underscoring this complex choreography, 1/3 of all human birth defects affect craniofacial development. Both orofacial clefting and malocclusions are common birth abnormalities that affect the midface. During midfacial development, regulatory genes control the dynamics of transcriptional activity, tissue patterning, and intercellular signaling to modulate the timing of morphogenetic and growth processes. Variation in these dynamics underlies both evolutionary divergence in midfacial outgrowth and the etiology of craniofacial birth defects. In non‐avians, the main variable driving species‐specific midfacial length is the maxilla of the upper jaw, while in avians it is the premaxilla. Also, avians have cleft palate in physiological conditions. Despite the availability of datasets of regulatory elements from craniofacial tissues and cranial neural crest cells, the majority of regulatory networks that control embryonic midfacial outgrowth are unknown with respect to their in vivo spatiotemporal context‐dependence. We are establishing regulatory landscapes that control different morphogenetic and outgrowth characteristics of midfacial elements at the organismal level in chick, mouse, and pig embryos, species characterized by remarkably different midfacial lengths. To this end, we are combining 3D gene expression profiles obtained via High Resolution Episcopic Microscopy (HREM) of embryos processed by whole mount in situ hybridization as well as genome‐wide transcriptional regulatory activity and epigenetic regulation assessed by RNA Seq, ATAC‐Seq, and chromatin mark ChIP‐Seq of embryonic midfacial anlagen. By this approach, we have identified candidate genes that regulate maxillary‐specific morphogenetic programs in avians versus mammals. One of these genes, which encodes a transcription factor (TF) bearing zinc finger motifs and a homeobox motif, is expressed meristically along the AP palatal shelf of mouse embryos at E11.5–14.5, but is not expressed in the palatal shelves of avian embryos at the corresponding developmental stages. Mice we generated with CRISPR/Cas‐mediated loss‐of‐function of this TF show cleft palate and stunted snout. Strikingly, children with a deletion of this TF exhibit high‐arched palate and cleft palate. These findings establish mechanisms underlying tolerance to morphological variation that separate normal development and evolution of craniofacial features from malformations associated with birth defects. 
Support or Funding Information: 
UCSF Recruitment Fund

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Regulatory Dynamics of Midfacial Growth in Evolution and Disease

https://escholarship.org/uc/item/59s3224z

Regulatory Dynamics of Midfacial Growth in Evolution and Disease

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eScholarship - University of California