Biology subjects

Franks, N. E.

Publications and source records attributed to Franks, N. E..

4 recordsLinked to original sources

bioRxiv2024

Hedgehog-dependent and Hedgehog-independent roles for Growth Arrest Specific 1 in mammalian kidney morphogenesis

Growth arrest specific 1 (GAS1) is a key regulator of mammalian embryogenesis, best known for its role in Hedgehog (HH) signaling, but with additional described roles in the FGF, RET, and NOTCH pathways. Previous work indicated a later role for GAS1 in kidney development through FGF pathway modulation. Here, we demonstrate that GAS1 is essential for both mesonephrogenesis and metanephrogenesis- most notably, Gas1 deletion in mice results in renal agenesis in a genetic background-dependent fashion. Mechanistically, GAS1 promotes mesonephrogenesis in a HH-dependent fashion, performing a unique co-receptor function, while promoting metanephrogenesis in a HH-independent fashion, acting as a putative secreted RET co-receptor. Our data indicate that Gas1 deletion leads to renal agenesis through a transient reduction in metanephric mesenchyme proliferation- a phenotype that can be rescued by exogenous RET pathway stimulation. Overall, this study indicates that GAS1 contributes to early kidney development through the integration of multiple different signaling pathways.

developmental biology↗

bioRxiv2023

Distinct expression patterns of Hedgehog signaling components in mouse gustatory system during postnatal tongue development and adult homeostasis

It is well established that the Hedgehog (HH) pathway regulates embryonic development of anterior tongue taste fungiform papilla (FP) and the posterior circumvallate (CVP) and foliate (FOP) taste papillae, and taste organ maintenance and regeneration in adults. However, there are knowledge gaps in determining HH signaling regulation in postnatal taste organ differentiation and maturation. Importantly, the HH transcription factors GLI1, GLI2 and GLI3 have not been investigated in early postnatal stages; and, the receptors PTCH1, GAS1, CDON and HHIP, required to either drive HH pathway activation or antagonism, remain unexplored. Using lacZ reporter mouse models, we mapped expression of the HH ligand SHH, receptors, and transcription factors in FP, CVP and FOP in early and late postnatal and adult stages. In adults we also studied the soft palate, and the geniculate and trigeminal ganglia which extend afferent fibers to the anterior tongue. Shh and Gas1 are the only components that were consistently expressed within taste buds of all three papillae and the soft palate. In the first postnatal week, we observed a broad expression of HH signaling components in FP and adjacent, non-taste filiform (FILIF) papillae in epithelium or stroma and tongue muscles. Remarkably, we observed elimination of Gli1 in FILIF and Gas1 in muscles, and downregulation of Ptch1 in lingual epithelium and of Cdon, Gas1 and Hhip in stroma from late postnatal stage. Further, HH receptor expression patterns in CVP and FOP epithelium differed from anterior FP. Among all the components, only known positive regulators of HH signaling, SHH, Ptch1, Gli1 and Gli2, were expressed in the ganglia. Our studies emphasize differential regulation of HH signaling in distinct postnatal developmental periods and in anterior versus posterior taste organs, and lay the foundation for functional studies to understand the roles of numerous HH signaling components in postnatal tongue development.

developmental biology↗

bioRxiv2022

Gli2 and Gli3 Regulate Horizontal Basal Cell-Mediated Regeneration of the Olfactory Epithelium

The olfactory epithelium (OE) is a specialized neuroepithelium that is replenished by two stem cell populations: globose basal cells (GBCs) and horizontal basal cells (HBCs). Previous work indicated that HBCs contain primary cilia, organelles that mediate Hedgehog (HH) pathway activity. However, a role for HH signaling in HBCs has not been investigated. We find that GLI2 and GLI3, transcriptional effectors of the HH pathway, are expressed in HBCs in the adult OE and that their expression expands following injury. Further, Gli2-expressing descendants contribute to all major OE cell types during OE regeneration. HBC-specific expression of constitutively active GLI2 drives inappropriate HBC proliferation, alters HBC identity, and culminates in a failure of HBCs to differentiate into olfactory sensory neurons (OSNs) following injury. HBC- specific deletion of endogenous Gli2 and Gli3 results in decreased HBCs and OSNs following OE injury. These data identify GLI2 and GLI3 as key regulators of HBC-mediated OE regeneration.

cell biology↗

bioRxiv2021

Plexins Promote Hedgehog Signaling Through Their Cytoplasmic GAP Activity

Hedgehog signaling controls tissue patterning during embryonic and postnatal development and continues to play important roles throughout life. Characterizing the full complement of Hedgehog pathway components is essential to understanding its wide- ranging functions. Previous work has identified Neuropilins, established Semaphorin receptors, as positive regulators of Hedgehog signaling. Neuropilins require Plexin co- receptors to mediate Semaphorin signaling, but a role for Plexins in Hedgehog signaling has not yet been explored. Here, we provide evidence that multiple Plexins promote Hedgehog signaling in NIH/3T3 fibroblasts and that Plexin loss-of-function in these cells results in significantly reduced Hedgehog pathway activity. Catalytic activity of the Plexin GTPase activating protein (GAP) domain is required for Hedgehog signal promotion, and constitutive activation of the GAP domain further amplifies Hedgehog signaling. Additionally, we demonstrate that Plexins promote Hedgehog signaling at the level of GLI transcription factors and that this promotion requires intact primary cilia. Finally, we find that Plexin loss-of-function significantly reduces the response to Hedgehog pathway activation in the mouse dentate gyrus. Together, these data identify Plexins as novel components of the Hedgehog pathway and provide insight into their mechanism of action.

developmental biology↗