Summary: Researchers have uncovered the crucial role of a protein subunit, INST10, in guiding pluripotent stem cells toward becoming neural cells during early development. The study found that diminished INST10 levels caused cells to lose neural identity and shift toward other fates, such as mesenchymal or intestinal cells.
These findings highlight INST10’s importance in maintaining neuronal identity and provide insights into the molecular processes underpinning neurogenesis. This research offers new perspectives for understanding neurodevelopmental disorders linked to mutations in the Integrator protein complex.
Key Facts:
- INST10, part of the Integrator protein complex, is essential for neural cell identity.
- Reduced INST10 causes cells to lose neural traits and adopt alternate cell fates.
- Findings link Integrator subunits to neurodevelopmental disorders and neurogenesis.
Source: Wistar Institute
The Wistar Institute’s Alessandro Gardini, Ph.D., and lab have shed new light on how certain biological processes determine the development of neural cells.
Their findings on a molecular “bridge” complex demonstrate a new level of detail in the understanding of early neural development — which is fundamental for the further understanding of neurodevelopmental syndromes.
The new paper, “The enhancer module of integrator controls cell identity and early neural fate commitment” was published in the journal, Nature Cell Biology.
“By achieving a better understanding of how the nervous system develops at the earliest level, we are better positioned to assess the causes of and potential solutions to neurodevelopmental disorders. Our research provides valuable evidence that neural cell development is not solely driven by transcription factors” said Dr. Gardini.
Although every cell in our body carries the same genetic information, not every cell is identical. Cells get direction on what type of cell to become: muscle cells, blood cells, neurons, etc.
In the early stages of biological development, stem cells transition from a state of “pluripotency,” which is the ability of an unspecialized cell to develop into any number of mature, specialized cell types based on the biological signals and inputs they receive along the way.
Dr. Alessandro Gardini was interested in the signals and inputs that cause pluripotent stem cells to commit to developing into neural cells during the process of “neurogenesis”: the formation of the human nervous system, including the brain.
Human neurogenesis is not fully understood, but certain mutations within subunits of a protein complex called Integrator–which influences neurogenesis–have been associated with neurodevelopmental disorders.
Gardini and his team assessed the Integrator subunit INST10, which, across cells from both the central and peripheral nervous systems, was more abundant than other subunits of the same Integrator protein complex; this confirmed that neural cells had some essential need for INST10.
Using a cell model that emulates early neural development, the researchers confirmed that cells with diminished INST10 not only exhibit very different gene-expression signatures — they also appeared to be drifting away from developing into neural cells and toward developing into mesenchymal cells, a confirmation that the presence of INST10 maintains the cellular identity of neurons.
At the single-cell level of analysis, the stem cell lines with decreased INST10 lost expression of “master neuronal genes” even as they gained gene expression signatures consistent with programming for becoming intestinal or smooth-tissue cells.
These findings confirmed that INST10 is critical to maintaining the cellular identities of neural cells, both during initial development and throughout the cell’s life.
Funding: National Institutes of Health grants R01HL141326, R01CA252223, T32CA09171, supplement HL141326-S1, and Ruth L. Kirschstein National Research Service Award F31 CA265257. This study was funded by grants from the G. Harold and Leila Y. Mathers Charitable Foundation.
About this genetics, neurodevelopment, and neurogenesis research news
Author: Steven Schneible
Source: Wistar Institute
Contact: Steven Schneible – Wistar Institute
Image: The image is credited to Neuroscience News
Original Research: Closed access.
“Wistar Institute Scientists Identify Important Factor in Neural Development” by Alessandro Gardini et al. Nature Cell Biology
Abstract
Wistar Institute Scientists Identify Important Factor in Neural Development
Lineage-specific transcription factors operate as master orchestrators of developmental processes by activating select cis-regulatory enhancers and proximal promoters.
Direct DNA binding of transcription factors ultimately drives context-specific recruitment of the basal transcriptional machinery that comprises RNA polymerase II (RNAPII) and a host of polymerase-associated multiprotein complexes, including the metazoan-specific Integrator complex.
Integrator is primarily known to modulate RNAPII processivity and to surveil RNA integrity across coding genes.
Here we describe an enhancer module of Integrator that directs cell fate specification by promoting epigenetic changes and transcription factor binding at neural enhancers.
Depletion of Integrator’s INTS10 subunit upends neural traits and derails cells towards mesenchymal identity. Commissioning of neural enhancers relies on Integrator’s enhancer module, which stabilizes SOX2 binding at chromatin upon exit from pluripotency.
We propose that Integrator is a functional bridge between enhancers and promoters and a main driver of early development, providing new insight into a growing family of neurodevelopmental syndromes.
