ROCK-nmMyoII, Notch and Neurog3 gene-dosage link epithelial morphogenesis with cell fate in the pancreatic endocrine-progenitor niche

Abstract

During mouse pancreas organogenesis, endocrine cells are born from progenitors residing in an epithelial plexus niche. After a period in a lineage-primed state, progenitors become endocrine committed via upregulation of We find that the to transition is associated with distinct stages of an epithelial egression process: narrowing the apical surface of the cell, basalward cell movement and eventual cell-rear detachment from the apical lumen surface to allow clustering as nascent islets under the basement membrane. Apical narrowing, basalward movement and transcriptional upregulation still occur without Neurog3 protein, suggesting that morphogenetic cues deployed within the plexus initiate endocrine commitment upstream or independently of Neurog3. Neurog3 is required for cell-rear detachment and complete endocrine-cell birth. The ROCK-nmMyoII pathway coordinates epithelial-cell morphogenesis and the progression through-expressing states. NmMyoII is necessary for apical narrowing, basalward cell displacement and upregulation, but all three are limited by ROCK activity. We propose that ROCK-nmMyoII activity, gene-dose and Notch signaling integrate endocrine fate allocation with epithelial plexus growth and morphogenesis, representing a feedback control circuit that coordinates morphogenesis with lineage diversification in the endocrine-birth niche.

Inducible Mosaic Cell Labeling Provides Insights Into Pancreatic Islet Morphogenesis

“…Movement of islet progenitors and beta cells has been observed in pancreatic explant studies, and protrusions have been reported in cells emerging from the duct ( Puri and Hebrok, 2007 ; Kesavan et al, 2014 ; Bechard et al, 2016 ; Pauerstein et al, 2017 ; Bankaitis et al, 2018 ). Based on these studies, it was thought that differentiated endocrine cells first move away from the duct into the mesenchyme and then cluster to form islets ( Bakhti et al, 2019 ).…”

“…While previous work suggested that progenitors actively migrate through the pancreatic mesenchyme during islet morphogenesis (Puri and Hebrok, 2007;Kesavan et al, 2014;Pauerstein et al, 2017), recent evidence reveals that clustering occurs in proximity to the pancreatic duct, either concurrent with cell exit (Sharon et al, 2019), or following movements along the ductal epithelium (Nyeng et al, 2019). Imaging studies in vivo and in explants have reported formation of dynamic protrusions in endocrine cells (Bechard et al, 2016;Bankaitis et al, 2018;Freudenblum et al, 2018), but their role in islet formation has not been fully defined.…”

Wnt signaling: implications in endoderm development and pancreas organogenesis

“…This occurs by producing and secreting non-canonical Wnt5a by mesenchyme that in turn triggers the expression of Wnt inhibitors Sfrp3 and Dkk1 in endocrine progenitors for endocrine fate allocation (Figure 3 Non-canonical Wnt signaling is well-known to establish planar cell polarity and is essential for tissue morphogenesis and architecture. There is accumulating evidence that the polarity, morphogenesis and differentiation of endocrine cells are tightly interlinked [52,53]. For instance, EGFR signaling through PI3K…”

Comprehensive single cell mRNA profiling reveals a detailed roadmap for pancreatic endocrinogenesis

“…Further differentiation of Ngn3 high precursors generates distinct endocrine subtypes of the aforementioned hormone-expressing lineages. Changes in the gene regulatory networks, extracellular signaling cues from the respective niche and epithelial states (non-polarized versus polarized and epithelialized) cooperatively orchestrate the specification and determination of EPs (Apelqvist, 1999;Arda et al, 2013;Bankaitis et al, 2015Bankaitis et al, , 2018Cortijo et al, 2012;Löf-Öhlin et al, 2017). Yet, during progressive lineage restriction from specified EP progenitors to determined EP precursors the molecular signature changes over time and the mechanisms underpinning lineage allocation towards a specific endocrine subtype fate have remained largely elusive.…”