A systems-level approach reveals new gene regulatory modules in the developing ear

Abstract

The inner ear is a complex vertebrate sense organ, yet it arises from a simple epithelium, the otic placode. Specification towards otic fate requires diverse signals and transcriptional inputs that act sequentially and/or in parallel. Using the chick embryo, we uncover novel genes in the gene regulatory network underlying otic commitment and reveal dynamic changes in gene expression. Functional analysis of selected transcription factors reveals the genetic hierarchy underlying the transition from progenitor to committed precursor, integrating known and novel molecular players. Our results not only characterize the otic transcriptome in unprecedented detail, but also identify new gene interactions responsible for inner ear development and for the segregation of the otic lineage from epibranchial progenitors. By recapitulating the embryonic programme, the genes and genetic sub-circuits discovered here might be useful for reprogramming naïve cells towards otic identity to restore hearing loss.

Lsd1 interacts with cMyb to demethylate repressive histone marks and maintain inner ear progenitor identity

“…Tyrode's saline supplemented with penicillin streptomycin was applied to the embryo, the egg was resealed with tape and incubated to the appropriate stage. Placodes were dissected as described previously (Anwar et al, 2017;Chen et al, 2017).…”

“…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.…”

Setting off the Alarms:Candida albicansElicits Pro-Inflammatory Differential Gene Expression in Intestinal Peyer’s Patches

“…NanoString analysis was performed in duplicate per experimental condition with the nCounter Analysis System using PanCancer Immune profiling kit. The results were analyzed using raw counts with DEseq2 (86, 87). A transcript was considered differentially expressed when it was up or downregulated at least 2-fold and had a P -adj value of <=0.05.…”

Notch signalling regulates epibranchial placode patterning and segregation

“…We next addressed the question of how the pool of Pax2 + PPA progenitors may segregate into three discrete epibranchial placodes as well as interplacodal pharyngeal ectodermal cells. We first investigated the spatiotemporal patterning of the epibranchial placodes from E8.5 to E9.5 using a series of placodal and pharyngeal markers including Eya1 and Six1 ( placodal progenitor markers); Neurog2 (the earliest pre-neural marker in epibranchial placode; Fode et al, 1998); Sox2 (essential for epibranchial neural competence; Gou et al, 2018;Tripathi et al, 2009); Irx5 (expressed in PPA; Feijoo et al, 2009;Glavic et al, 2004); vestigial-like2 (Vgll2) (expressed in the pharyngeal region; Chen et al, 2017;Johnson et al, 2011); Fgf3; and the FGF downstream target Etv5 (essential for pharyngeal morphogenesis) (Urness et al, 2011).…”