Biology subjects

Paulding, D.

Publications and source records attributed to Paulding, D..

2 recordsLinked to original sources

bioRxiv2025

Perdurant TTC21B protein in the early mouse embryo is required for proper forebrain neural progenitor proliferation.

Primary cilia play a pivotal role in cellular signaling and development and disruptions in ciliary form and/or function leads to human ciliopathies. Here, we examine the role of Ttc21b, a key component of the intraflagellar transport-A complex, in mouse forebrain development using a Ttc21balien null allele. Our findings reveal significant microcephaly in homozygous mutants is caused by disrupted neural progenitor proliferation and differentiation. Histological and immunohistochemical analyses show an enlarged ventricular zone and reduced cortical plate thickness, accompanied by altered mitotic spindle angles, suggesting defects in symmetric versus asymmetric cell divisions. Despite low Ttc21b expression in the forebrain epithelium, early embryonic expression patterns imply that perdurant TTC21B protein may underlie these phenotypes. Progenitor proliferation kinetics were disrupted, with fewer cells re-entering the cell cycle, correlating with reduced TBR2-positive intermediate progenitors and altered neurogenesis dynamics. Neuronal processes in the cortical plate were significantly shortened, suggesting cytoskeletal defects specific to terminal differentiation stages. Our findings support a model where early Ttc21b expression in precursors destined for the forebrain is critical for sustaining later neural progenitor proliferation and differentiation. These results advance our understanding of primary cilia in cortical development and provide a framework for exploring cytoskeletal contributions to ciliopathies.

developmental biology↗

bioRxiv2019

Nubp2 is required for cranial neural crest survival in the mouse.

The N-ethyl-N-nitrosourea (ENU) forward genetic screen is a useful tool for the unbiased discovery of novel mechanisms regulating developmental processes. We recovered the dorothy mutation in such a screen designed to recover recessive mutations affecting craniofacial development in the mouse. Dorothy embryos die prenatally and exhibit many striking phenotypes commonly associated with ciliopathies, including a severe midfacial clefting phenotype. We used exome sequencing to discover a missense mutation in Nucleotide Binding Protein 2 (Nubp2) to be causative. This finding was confirmed with a complementation analysis between the dorothy allele and a Nubp2 null allele (Nubp2Null). We demonstrate that Nubp2 is indispensable for embryogenesis. NUBP2 is implicated in both the Cytosolic Iron/Sulfur cluster Assembly (CIA) pathway and in the negative regulation of ciliogenesis. Conditional ablation of Nubp2 in the neural crest lineage with Wnt1-cre recapitulates the dorothy craniofacial phenotype. Using this model, we found that the proportion of ciliated cells in the craniofacial mesenchyme was unchanged, and that markers of the Shh, Fgf, and Bmp signaling pathways are unaltered. Finally, we show that the phenotype results from a marked increase in apoptosis within the craniofacial mesenchyme.\n\nSummary StatementAn ENU screen identifies a novel allele of Nubp2 which is then demonstrated to be required for cranial neural crest survival and proper midfacial development.

developmental biology↗