A gene network regulated by FGF signalling during ear development

Abstract

During development cell commitment is regulated by inductive signals that are tightly controlled in time and space. In response, cells activate specific programmes, but the transcriptional circuits that maintain cell identity in a changing signalling environment are often poorly understood. Specification of inner ear progenitors is initiated by FGF signalling. Here, we establish the genetic hierarchy downstream of FGF by systematic analysis of many ear factors combined with a network inference approach. We show that FGF rapidly activates a small circuit of transcription factors forming positive feedback loops to stabilise otic progenitor identity. Our predictive network suggests that subsequently, transcriptional repressors ensure the transition of progenitors to mature otic cells, while simultaneously repressing alternative fates. Thus, we reveal the regulatory logic that initiates ear formation and highlight the hierarchical organisation of the otic gene network.

Spatial and temporal inhibition of FGFR2b ligands reveals continuous requirements and novel targets in mouse inner ear morphogenesis

“…The identification of several FGFR2b target genes not implicated previously in ear development or hearing loss syndromes provides a tantalizing glimpse into a new set of potential otocyst morphogenetic factors. Given the novelty of these targets, it is tempting to speculate that previously unappreciated regulatory pathways may be at play during otic morphogenesis, as has been postulated for otic placode induction (Anwar et al, 2017). Functional studies will be required to address the roles of each of these new genes.…”

LSD1 interacts with cMYB to demethylate repressive histone marks and maintains inner ear progenitor identity

“…In the developing embryo, multipotent progenitors are able to maintain their identity and gene expression programmes despite ongoing changes in their signalling environment. We have recently uncovered a gene network that integrates signalling inputs and transcriptional activity during the transition from progenitor to committed inner ear cells (Anwar et al, 2017;Chen et al, 2017), providing a good basis to explore this problem in a well-defined system. The entire inner ear is derived from a simple epithelium, the otic placode, located in the ectoderm next to the hindbrain.…”

“…The entire inner ear is derived from a simple epithelium, the otic placode, located in the ectoderm next to the hindbrain. Prior to placode formation, otic precursors are part of a sensory progenitor pool (the pre-placodal region, PPR), from which FGF signalling induces otic-epibranchial progenitors (OEPs) (Anwar et al, 2017;Ladher et al, 2000;Maroon et al, 2002;Martin and Groves, 2006;Sun et al, 2007;Urness et al, 2010;Wright and Mansour, 2003). Over time, OEPs segregate into committed ear and epibranchial cells.…”

Neural crest and the origin of species‐specific pattern

“…Members and targets of the FGF, BMP, WNT, and other pathways mediate complex signaling interactions among the developing placodes, mesoderm, endoderm, and the neural crest, which in turn lead to the differential activation of placode-specific sets of transcription factors (Anwar, Tambalo, Ranganathan, Grocott, & Streit, 2017;Baker, Stark, Marcelle, & Bronner-Fraser, 1999;Brunskill et al, 2014;Depew et al, 1999;Grocott, Johnson, Bailey, & Streit, 2011;Groves & Bronner-Fraser, 2000;Hintze et al, 2017;Jourdeuil & Taneyhill, 2018;Ladher, 2017;Ladher, Wright, Moon, Mansour, & Schoenwolf, 2005;McLarren, Litsiou, & Streit, 2003;Moody & LaMantia, 2015;Saint-Jeannet & Moody, 2014;Steventon, Mayor, & Streit, 2014;Yang et al, 2013). In almost all of these cases, the neural crest plays an obligatory role during proper patterning and differentiation.…”