Recent highlights
Complete list of publications on NCBI
Fgf8 regulates first pharyngeal arch segmentation through pouch-cleft interactions Front Cell Dev Biol (2023)
Nathaniel Zbasnik and Jennifer L. Fish
Introduction: The pharyngeal arches are transient developmental structures that, in vertebrates, give rise to tissues of the head and neck. A critical process underlying the specification of distinct arch derivatives is segmentation of the arches along the anterior-posterior axis. Formation of ectodermal-endodermal interfaces is a key mediator of this process, and although it is essential, mechanisms regulating the establishment of these interfaces vary between pouches and between taxa. Methods: Here, we focus on the patterning and morphogenesis of epithelia associated with the first pharyngeal arch, the first pharyngeal pouch (pp1) and the first pharyngeal cleft (pc1), and the role of Fgf8 dosage in these processes in the mouse model system. Results: We find that severe reductions of Fgf8 levels disrupt both pp1 and pc1 development. Notably, out-pocketing of pp1 is largely robust to Fgf8 reductions, however, pp1 extension along the proximal-distal axis fails when Fgf8 is low. Our data indicate that Fgf8 is required for specification of regional identity in both pp1 and pc1, for localized changes in cell polarity, and for elongation and extension of both pp1 and pc1.
Discussion: Based on Fgf8-mediated changes in tissue relationships between pp1 and pc1, we hypothesize that extension of pp1 requires physical interaction with pc1. Overall, our data indicate a critical role for the lateral surface ectoderm in segmentation of the first pharyngeal arch that has previously been under-appreciated.
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Fgf8 dosage regulates jaw shape and symmetry through pharyngeal-cardiac tissue relationships Dev Dyn (2022)
Zbasnik N, Dolan K, Buczkowski SA, Green RM, Hallgrímsson B, Marcucio RS, Moon AM, Fish JL
Asymmetries in craniofacial anomalies are commonly observed. In the facial skeleton, the left side is more commonly and/or severely affected than the right. Such asymmetries complicate treatment options. Mechanisms underlying variation in disease severity between individuals as well as within individuals (asymmetries) are still relatively unknown. Developmental reductions in fibroblast growth factor 8 (Fgf8) have a dosage dependent effect on jaw size, shape, and symmetry. Further, Fgf8 mutants have directionally asymmetric jaws with the left side being more affected than the right. Defects in lower jaw development begin with disruption to Meckel's cartilage, which is discontinuous. All skeletal elements associated with the proximal condensation are dysmorphic, exemplified by a malformed and misoriented malleus. At later stages, Fgf8 mutants exhibit syngnathia, which falls into two broad categories: bony fusion of the maxillary and mandibular alveolar ridges and zygomatico-mandibular fusion. All of these morphological defects exhibit both inter- and intra-specimen variation. We hypothesize that these asymmetries are linked to heart development resulting in higher levels of Fgf8 on the right side of the face, which may buffer the right side to developmental perturbations. This mouse model may facilitate future investigations of mechanisms underlying human syngnathia and facial asymmetry.
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Satb2 regulates proliferation and nuclear integrity of pre-osteoblasts. Bone (2019)
Todd Dowrey, Evelyn E. Schwager, Julieann Duong, Fjodor Merkuri, Yuri A Zarate, and Jennifer L. Fish
Special AT-rich sequence binding protein 2 (Satb2) is a matrix attachment region (MAR) binding protein. Satb2 impacts skeletal development by regulating gene transcription required for osteogenic differentiation. Although its role as a high-order transcription factor is well supported, other roles for Satb2 in skeletal development remain unclear. In particular, the impact of dosage sensitivity (heterozygous mutations) and variance on phenotypic severity is still not well understood. To further investigate molecular and cellular mechanisms of Satb2-mediated skeletal defects, we used the CRISPR/Cas9 system to generate Satb2 mutations in MC3T3-E1 cells. Our data suggest that, in addition to its role in differentiation, Satb2 regulates progenitor proliferation. We also find that mutations in Satb2 cause chromatin defects including nuclear blebbing and donut-shaped nuclei. These defects may contribute to a slight increase in apoptosis in mutant cells, but apoptosis is insufficient to explain the proliferation defects. Satb2 expression exhibits population-level variation and is mostly highly expressed from late G1 to late G2. Based on these data, we hypothesize that Satb2 may regulate proliferation through two separate mechanisms. First, Satb2 may regulate the expression of genes necessary for cell cycle progression in pre-osteoblasts. Second, similar to other MAR-binding proteins, Satb2 may participate in DNA replication. We also hypothesize that variation in the severity or penetrance of Satb2-mediated proliferation defects is due to stochastic variation in Satb2 binding to DNA, which may be buffered in some genetic backgrounds. Further elucidation of the role of Satb2 in proliferation has potential impacts on our understanding of both skeletal defects and cancer.
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Developmental processes regulate craniofacial variation in disease and evolution. genesis (2018)
Fjodor Merkuri and Jennifer L. Fish
Variation in development mediates phenotypic differences observed in evolution and disease. Although the mechanisms underlying phenotypic variation are still largely unknown, recent research suggests that variation in developmental processes may play a key role. Developmental processes mediate genotype‐phenotype relationships and consequently play an important role regulating phenotypes. In this review, we provide an example of how shared and interacting developmental processes may explain convergence of phenotypes in spliceosomopathies and ribosomopathies. These data also suggest a shared pathway to disease treatment. We then discuss three major mechanisms that contribute to variation in developmental processes: genetic background (gene‐gene interactions), gene‐environment interactions, and developmental stochasticity. Finally, we comment on evolutionary alterations to developmental processes, and the evolution of disease buffering mechanisms.
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Developmental nonlinearity drives phenotypic robustness. Nature Communications (2017)
Rebecca M. Green*, Jennifer L. Fish*, Nathan M. Young, Francis J. Smith, Benjamin Roberts, Katie Dolan, Irene Choi, Courtney Leach, Paul Gordon, James M. Cheverud, Charles C. Roseman, Trevor J. Williams, Ralph S. Marcucio+, Benedikt Hallgrimsson+
Robustness to perturbation is a fundamental feature of complex organisms. Mutations are the raw material for evolution, yet robustness to their effects is required for species survival. The mechanisms that produce robustness are poorly understood. Nonlinearities are a ubiquitous feature of development that may link variation in development to phenotypic robustness. Here we manipulate the gene dosage of a signaling molecule, Fgf8, a critical regulator of vertebrate development. We demonstrate that variation in Fgf8 expression has a nonlinear relationship to phenotypic variation, predicting levels of robustness among genotypes. Differences in robustness are not due to gene expression variance or dysregulation, but emerge from the nonlinearity of the genotype-phenotype curve. In this instance, embedded features of development explain robustness differences. How such features vary in natural populations and relate to genetic variation are key questions for unravelling the origin and evolvability of this feature of organismal development.
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SATB2-associated syndrome: Mechanisms, phenotype, and practical recommendations. Am. J. Med. Genet. A (2017)
Yuri A. Zarate and Jennifer L. Fish
The SATB2-associated syndrome is a recently described syndrome characterized by developmental delay/intellectual disability with absent or limited speech development, craniofacial abnormalities, behavioral problems, dysmorphic features, and palatal and dental abnormalities. Alterations of the SATB2 gene can result from a variety of different mechanisms that include contiguous deletions, intragenic deletions and duplications, translocations with secondary gene disruption, and point mutations. The multisystemic nature of this syndrome demands a multisystemic approach and we propose evaluation and management guidelines. The SATB2-associated syndrome registry has now been started and that will allow gathering further clinical information and refining the provided surveillance recommendations.
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Evolvability of the vertebrate craniofacial skeleton. Seminars in Cell & Developmental Biology (2017)
Jennifer L. Fish
The skull is a vertebrate novelty. Morphological adaptations of the skull are associated with major evolutionary transitions, including the shift to a predatory lifestyle and the ability to masticate while breathing. These adaptations include the chondrocranium, dermatocranium, articulated jaws, primary and secondary palates, internal choanae, the middle ear, and temporomandibular joint. The incredible adaptive diversity of the vertebrate skull indicates an underlying bauplan that promotes evolvability. Comparative studies in craniofacial development suggest that the craniofacial bauplan includes three secondary organizers, two that are bilaterally placed at the Hinge of the developing jaw, and one situated in the midline of the developing face (the FEZ). These organizers regulate tissue interactions between the cranial neural crest, the neuroepithelium, and facial and pharyngeal epithelia that regulate the development and evolvability of the craniofacial skeleton.
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Developmental mechanisms underlying variation in craniofacial disease and evolution. Developmental Biology (2016)
Jennifer L. Fish
Craniofacial disease phenotypes exhibit significant variation in penetrance and severity. Although many genetic contributions to phenotypic variation have been identified, genotype-phenotype correlations remain imprecise. Recent work in evolutionary developmental biology has exposed intriguing developmental mechanisms that potentially explain incongruities in genotype-phenotype relationships. This review focuses on two observations from work in comparative and experimental animal model systems that highlight how development structures variation.
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Multiple Developmental Mechanisms Regulate Species-Specific Jaw Size. Development (2014)
Jennifer L. Fish, Rachel S. Sklar, Katherine C. Woronowicz, Richard A. Schneider
Jaw variation and development has played a crucial role in adaptive radiation of vertebrates and often associated with disease. To test the hypothesis that early events regulating Neural Crest Cell progenitors contribute to species specificity, we compared the causes for the remarkable differences observed between Duck and Quail jaw sizes.
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