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The proteasome subunit psmb1 is essential for craniofacial cartilage maturation and morphogenesis

ABSTRACT: Craniofacial dysmorphisms are among the most common birth defects. Proteasome mutations frequently result in craniofacial dysmorphisms including lower jaw malformations; however, the underlying mechanisms are unknown. Here we use a zebrafish proteasome subunit beta 1 (psmb1) mutant to define the cellular mechanisms underlying proteasome mutation-induced craniofacial dysmorphisms. psmb1 mutants exhibit a flattened ceratohyal and smaller Meckel’s and palatoquadrate cartilages. Ceratohyal flattening is a result of failed chondrocyte convergent extension, accompanied by reduced numbers of chondrocytes in the lower jaw due to defects in chondrocyte differentiation. Morphogenesis of craniofacial muscles and tendons is similarly perturbed. psmb1 mutants lack the hyohyal muscles and craniofacial tendons are shortened and disorganized. We additionally identify a critical period for proteasome function in craniofacial development, specifically during chondrocyte and muscle differentiation. psmb1 overexpression in sox10+ cells of mutant embryos rescued both cartilage and tendon phenotypes but induced only a partial rescue of the muscle phenotype, indicating that psmb1 is required in both tissue-autonomous and non-autonomous fashions during craniofacial development. Overall, our work demonstrates that psmb1 is required for craniofacial cartilage, tendon, and muscle differentiation and morphogenesis.

ORGANISM(S): Danio rerio

PROVIDER: GSE243072 | GEO | 2024/07/12

REPOSITORIES: GEO

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Project description:The tongue is a muscular organ in the vertebrate oral cavity that performs complex functions in daily life, including feeding and phonetic articulation. The tongue consists of mesenchyme cells of two distinct origins: the muscle cells are derived from occipital somites whereas the tendons and other connective tissues derived from the cranial neural crest. Cranial neural crest cells are important for the initiation of tongue swelling and proper patterning of intrinsic and extrinsic tongue muscle groups. However, little is known regarding the molecular and cellular mechanisms of tongue morphogenesis. We show that the odd-skipped related 1 (Osr1) transcription factor exhibits dynamic expression in the tongue mesenchyme during early tongue development. Tissue-specific inactivation of Osr1 in the early neural crest cells resulted in ectopic cartilage formation in the mouse tongue. We show that Sox9, the master regulator of chondrocyte differentiation, is initially widely expressed in the neural crest derived mesenchyme in the tongue and subsequently down-regulated concomitant by up-regulation of Osr1 expression. Osr1 mutant embryos exhibit persistent expression of Sox9 and chondrocyte differentiation from the neural crest derived tongue mesenchyme. Further biochemical analyses indicate that Osr1 may directly suppresses Sox9 gene expression in the tongue mesenchyme. These data reveal a novel mechanism in suppression of chondrogenic fate during tongue development. Remarkably, the ectopic cartilage in the Osr1 mutant mice resembles the entoglossal cartilage naturally develops in the avian tongue. These results suggest that modulation of expression of Osr1 may underline the evolutionary divergence in tongue cartilage formation. RNAs were isolated from microdissected E12 embryonic mouse tongue of Osr1f/-;Wnt1cre and control littermates and characterized by RNAseq E12 mouse embryonic tongues were micro-dissceted, 3 pairs of control and mutant samples were pooled for the RNA extraction

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The proteasome subunit psmb1 is essential for craniofacial cartilage maturation and morphogenesis

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