11/02/2022
By Nathaniel Zbasnik

The Kennedy College of Sciences, Department of Biological Sciences, invites you to attend a doctoral dissertation defense by Nathaniel Zbasnik on “The role of Fgf8 and pouch morphogenesis in jaw development and disease."

Ph.D. Candidate: Nathaniel Zbasnik
Date: Friday, Nov. 18, 2022
Time: 10 a.m.
Location: Olsen 410. Please contact Nathaniel_Zbasnik@student.uml.edu for Zoom link if you are interested in attending digitally.

Committee Members:

  • Jennifer L. Fish (advisor), Associate Professor, Biological Sciences Department, University of Massachusetts Lowell
  • Natalie Steinel, Assistant Professor, Biological Sciences Department, University of Massachusetts Lowell
  • Frederic Chain, Assistant Professor, Biological Sciences Department, University of Massachusetts Lowell
  • Susanna Remold, Professor, Biological Sciences Department, University of Massachusetts Lowell
  • Craig Albertson, Professor, Biology Department, University of Massachusetts Amherst

Abstract:
Jaws are a key characteristic that facilitated the radiation of the vertebrate clade by expanding dietary niches. Vertebrates exhibit diversity in jaw size and shape, indicating that jaw development facilitates evolvability while also being robust to perturbation, as malformations of the jaw influence organismal survivability. Jaws develop from the pharyngeal arches and involve contributions from neural crest (NC), cranial mesoderm, facial ectoderm, and the pharyngeal endoderm. The roles of NC and oral ectoderm in jaw development have been relatively well studied but the role of the pharyngeal endoderm, and more specifically, the pharyngeal pouches, has been relatively understudied, particularly in amniotes. It is, however, known that the first pharyngeal pouch (PP1) plays an essential role in jaw formation and helps form critical derivatives of the head. To better understand the role of PP1 in jaw development, I took a comparative developmental and genetic approach to examine the relationship between PP1 morphogenesis and jaw morphology. I quantified PP1 shape and regional identity in multiple vertebrate taxa. I examined Fgf8 tissue contributions to asymmetries in facial defects. Lastly, I quantified the effects of Fgf8 dosage on the morphogenesis of PP1.

I hypothesized that changes in pouch shape or regional identity are an underlying factor in jaw development contributing to differences in species specific jaw morphology among vertebrates. My data indicate that PP1 shapes are similar at earlier embryonic stages and diverge among taxa as embryos develop. Therefore, I argue that PP1 shapes share an early common developmental plan related to their role in pharyngeal patterning. Subsequently, differences in species specific derivatives of PP1, shape changes are observed later in development.

Craniofacial malformations exhibit variation in disease severity, which can also occur within individuals, exhibited as left-right asymmetry. Notably, unilateral clefts of the lip occur on the left side twice as often as clefts on the right side. It is unclear what mechanisms underlie this directional asymmetry. Fgf8 is expressed in the oral ectoderm of the PA1, lateral ectoderm of the pharyngeal clefts, the foregut endoderm of the pharyngeal pouches, and the anterior heart field mesoderm. PA1 is the precursor of jaws whereas the first PP1 and cleft contribute to the middle ear. To further investigate the role of Fgf8 in pharyngeal development, we utilized an allelic series of mutant mice, that generates embryos expressing different levels of Fgf8 during development, including a mild and severe mutant. Fgf8 mutant mice have directionally asymmetric jaws with the left side being more affected than the right. Further, the coronoid process is absent on both sides in our severe mutants but only on the left side in the mild mutants. Disruptions to patterning, exemplified by alterations to the position of the hinge or joint of the jaw is observed. We have also observed asymmetry in Fgf8 expression linked to heart development whereby heart looping results in heart-PA1 tissue interactions on the right side of the head. Taken together, our data indicate there may be an asymmetric contribution to facial development whereby higher levels of Fgf8 on the right side may promote accelerated development of the face in normal development as well as buffering of defects during disease. It was also quantified that PP1 morphogenesis of Fgf8 severe mutants contact the ectoderm but has variable deformities of the shape and proximo-distal extension. These defects correlate to defects of patterning, development of PP1, and the first pharyngeal cleft (PC1). Interestingly these deformities only occur in our severe mutants suggesting that low levels of Fgf8 are still sufficient for pouch growth and development.