summary: INSR, a protein essential for insulin activity, plays an important role in the longevity of stem cells. In addition, disruption of INSR in glioblastoma brain cancer stem cells leads to inhibition of growth of tumor-forming primordial cells.
A receptor first identified as essential for insulin action, also present in neural stem cells located deep in the brains of mice, is pivotal to the longevity of brain stem cells, according to the Rutgers study, a finding that has important implications for brain health and future treatments for brain disorders.
The study appears in the journal Stem Cell Reportsspecifies a specific protein known as the insulin receptor (INSR), which is abundant in neural stem cells located in the subventricular region of the brain.
During development, neural stem cells give rise to the entire nervous system, continuing into adulthood. Over the life span of these neural stem cells they produce new neurons and non-neuronal cells that maintain the brain’s infrastructure and functioning.
Separately, the scientists came up with another finding when examining brain tumors: INSR plays an important role in maintaining a group of specialized brain cancer cells known as glioblastoma stem cells (GBM). When they inhibited INSR in GBM stem cells, they inhibited the growth of those primitive tumor-forming cells.
“It is important to understand the molecular mechanisms necessary for brain stem cell growth and strength under normal and abnormal growth conditions,” said study author Stephen Levison, professor of neuroscience in the Department of Pharmacology, Physiology and Neuroscience and director. From the Laboratory of Regenerative Neurobiology at Rutgers College of Medicine, New Jersey.
“Understanding the signals that regulate these primitive cells could one day lead to new treatments for brain disorders.”
Several neurodegenerative disorders, such as multiple sclerosis, Parkinson’s disease, and Alzheimer’s disease, are associated with brain cell destruction, said co-author Theresa Wood, Distinguished Professor and Rena Warshaw Chair in Multiple Sclerosis in the Department of Pharmacology, Physiology, and Neuroscience at Rutgers New Jersey School of Medicine .
Wood, who teaches and conducts research at the New Jersey Cancer Institute, said.
Cellular receptors such as INSR are protein molecules found on cell surfaces. Substances, whether natural or man-made, that unlock the receptor’s “lock” can stimulate the cell to divide, differentiate, or die.
By identifying the receptors that perform these functions on specific cell types, and by understanding their structures and functions, scientists can design materials that act as switches for receptors, to turn them on or off.
Previous studies by this research team showed that a specific ‘switch’, a signaling protein known as insulin-like growth factor II (IGF-II), was needed to maintain neural stem cells in two locations of the adult brain. that harbor these primitive cells.
In the current experiment, the scientists were looking to identify the receptors. To do this, they used genetic tools that allowed them to delete the INSR and insert a fluorescent protein so that they could trace the neural stem cells and the cells that generate them.
They found that the number of neural stem cells in the subventricular region in the brains of mice lacking INSR collapsed.
Adult neurogenesis — the idea of producing new cells in the adult brain — has been a burgeoning area of scientific research since the late 1990s, when researchers confirmed what was just a theory in laboratory studies of the brains of humans, primates and birds. Adult neural stem cells are stem cells that can self-renew and produce new neurons, brain support cells, oligodendrocytes, and astrocytes.
“Given the widespread interest in stem cells as well as the interest in whether changes in adult stem cells may contribute to cancer, the findings of our research should be of interest,” Levison said.
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“Adult mouse subventricular neural stem cells require insulin receptors for self-renewal” by Shravanthi Chidambaram et al. Stem Cell Reports
Subventricular adult neural stem cells require insulin receptors for self-renewal
- The insulin receptor (INSR) is essential for the self-renewal of adult SVZ neural stem cells
- INSR deletion causes decreased sense of smell with increased olfactory bulb neurogenesis
- Hippocampal stem cells (and associated behaviors) do not require INSR
- Glioblastomas overexpress components of the INSR pathway required for tumor growth
The insulin receptor (INSR) is an evolutionarily conserved signaling protein that regulates cellular development and metabolism. INSR signaling promotes neurogenesis in fruit fly; However, a specific role for INSR in maintaining adult neural stem cells (NSCs) in mammals has not been investigated.
We show that the conditional deletion of a file INR The gene in adult mouse NSCs reduces NSCs in the subventricular region by 70% accompanied by a corresponding increase in progenitors.
INR The deletion also resulted in the olfactory deficiency caused by aberrant neurogenesis in the olfactory bulb. Interestingly, hippocampal neurons and hippocampal-dependent behaviors were not disturbed.
Glioblastomas exposed to the nervous system and mesenchyme had high INSR/insulin-like growth factor (IGF) pathway gene expression, and isolated glioblastoma stem cells had an abnormally high proportion of the INSR:IGF receptor type 1.
Furthermore it, INSR Knockdown inhibited GBM tumor growth. Altogether, these data demonstrate that INSR is essential for a subset of normal NSCs, as well as for brain tumor stem cell self-renewal.