Developmental cell fate choice employs two distinct cis regulatory strategies

Abstract

In many developing tissues the patterns of gene expression that assign cell fate are organised by secreted signals functioning in a graded manner over multiple cell diameters. Cis Regulatory Elements (CREs) interpret these graded inputs to control gene expression. How this is accomplished remains poorly understood. In the neural tube, a gradient of the morphogen Sonic hedgehog allocates neural progenitor identity. Here, we uncover two distinct ways in which CREs translate graded Shh signaling into differential gene expression. In the majority of ventral neural progenitors a common set of CREs are used to control gene activity. These CREs integrate cell type specific inputs to control gene expression. By contrast, the most ventral progenitors use a unique set of CREs. These are established by the pioneer factor FOXA2, paralleling the role of FOXA2 in endoderm. Moreover, FOXA2 binds a subset of the same sites in neural and endoderm cells. Together the data identify distinct cis regulatory strategies for the interpretation of morphogen signaling and raise the possibility of an evolutionarily conserved role for FOXA2-mediated regulatory strategy across tissues.

Mechanisms of robustness in gene regulatory networks involved in neural development

“…Shh binds to the receptor Ptc, inhibiting its repressive function over Smo, another membrane protein that subsequently triggers Shh signaling pathways. These pathways result in the activation of Gli transcription factors (TF), which drive chromatin remodeling and transcriptional regulation at different regulatory elements along the ventral-dorsal axis, inducing transcription of specific target genes (Vokes et al, 2008 ; Oosterveen et al, 2012 ; Delás et al, 2022 ). Remarkably, this includes a feedback loop through the upregulation of the PTCH1 gene, which codes for Ptc, resulting in an Shh-induced increase of Ptc levels (Goodrich et al, 1996 ; Marigo and Tabin, 1996 ; Sagner and Briscoe, 2017 ).…”