# Foxi1 regulates multipotent mucociliary progenitors and ionocyte specification through transcriptional and epigenetic mechanisms

## TL;DR

Foxi1 helps control the development of skin cells in frogs and is linked to human diseases, with new roles in maintaining cell identity and regulating cell fates.

## Contribution

The study reveals a novel role for Foxi1 in regulating mucociliary progenitor cells and ionocyte specification through concentration-dependent transcriptional and epigenetic mechanisms.

## Key findings

- Low Foxi1 levels maintain ectodermal competence in mucociliary progenitors via Notch signaling.
- High Foxi1 levels induce ionocyte specification in cooperation with Ubp1 and Dmrt2.
- Foxi1 expression is regulated through auto- and Notch-regulation, affecting mucociliary patterning.

## Abstract

Foxi1 is a master regulator of ionocytes (ISCs/INCs) across species and organs. Two subtypes of ISCs exist, and both α- and β-ISCs regulate pH- and ion-homeostasis in epithelia. Gain and loss of FOXI1 function are associated with human diseases, including Pendred syndrome, male infertility, renal acidosis, and cancers. Foxi1 was predominantly studied in the context of ISC specification, however, reports indicate additional functions in early and ectodermal development. Here, we re-investigated the functions of Foxi1 in Xenopus laevis embryonic mucociliary epidermis developpment and found a novel function for Foxi1 in the generation of Notch-ligand expressing mucociliary multipotent progenitors (MPPs). We demonstrate that MPPs are a distinct sub-population of epidermal cells in which Foxi1 has two concentration-dependent functions: At low levels, Foxi1 maintains ectodermal competence in MPPs through transcriptional and epigenetic mechanisms, while at high levels, Foxi1 induces a multi-step process of ISC specification and differentiation in cooperation with Ubp1 and Dmrt2. We further describe how foxi1 expression is affected through auto- and Notch-regulation, and how this developmental program affects mucociliary patterning. Together, we reveal novel functions for MPPs and Foxi1 in Xenopus mucociliary epidermis formation, relevant to our understanding of vertebrate development and human disease.

The transcription factor Foxi1 regulates ionocytes across species and organs and it is associated with several human diseases, but its function in epidermis remains unclear. This study shows that low concentrations of Foxi1 in progenitor cells maintain epidermal identity via the Notch pathway affecting mucociliary cell fates in Xenopus.