Summary: Gestational iron deficiency (GID) affects the behavior of embryonic progenitor cells, resulting in the creation of suboptimal networks of specialized neurons later in life.
Source: University of Rochester
The cells that make up the human brain begin to develop long before the physical form of the brain has formed. This early organization of a network of cells plays a major role in brain health throughout a lifetime.
Many studies have shown that mothers with low levels of iron during pregnancy have a higher risk of giving birth to a child who develops cognitive disorders like autism, attention deficit syndrome and cognitive disorders. ‘learning.
However, iron deficiency is still prevalent among pregnant women and young children.
The mechanisms by which gestational iron deficiency (GID) contributes to cognitive impairment are not fully understood. The lab of Margot Mayer-Proschel, PhD, professor of biomedical genetics and neuroscience at the University of Rochester Medical Center, was the first to demonstrate that the brains of animals born to iron-deficient mice respond abnormally to excitatory brain stimuli, and that iron supplements given at birth do not restore functional impairments that appear later in life.
More recently, his lab has made significant progress in finding the cellular origin of the deficiency and has identified a novel embryonic neural progenitor cell target for GID.
This study has just been published in the journal Development.
“We are very excited about this discovery,” said Mayer-Proschel, who received a $2 million grant from the National Institute of Child Health & Human Development in 2018 to do this work.
“This could link gestational iron deficiency to these very complex disorders. Understanding this connection could lead to changes in healthcare recommendations and potential targets for future therapies.
Build the map
Michael Rudy, PhD, and Garrick Salois, both graduate students in the lab and co-first authors of the study, worked backwards to make this connection. By examining the brains of adults and young mice born with a known GID, they discovered disruption of interneurons, cells that control the balance between excitation and inhibition and ensure that the mature brain can respond appropriately to incoming signals. .
These interneurons are known to develop in a specific region of the embryonic brain called the medial ganglionic eminence – where specific factors define the fate of early neural progenitor cells which then divide, migrate and mature into neurons that populate the developing cerebral cortex. .
The researchers found that this specific pool of progenitor cells was disrupted in embryonic brains exposed to GID.
These results provide evidence that GID affects the behavior of embryonic progenitor cells, causing a suboptimal network of specialized neurons to be created later in life.
“Looking back, we were able to identify when progenitor cells started acting differently in iron-deficient animals compared to iron-normal controls,” Mayer-Proschel said.
“This confirms that the correlation between cellular change and GID occurs early in the womb. Translating the timeline to humans would put it in the first three months of gestation before many women know they are pregnant.
Bringing the next model closer to humans
After identifying cellular targets in a mouse model of GID, Salois, a graduate student in neuroscience at the Mayer-Proschel lab, is currently establishing a human model of iron deficiency using brain organoids – a mass of cells, in this case that represents a brain.
These “mini-brains,” which look more like tiny balls that require a microscope to study, may be responsible for forming specific regions of the ganglionic eminences of the embryonic human brain. With these researchers can mimic the development of neuronal progenitor cells that are targeted by GID in mice.
“We believe that this model will not only allow us to determine the relevance of our discovery in the mouse model to the human system, but will also allow us to find new cellular targets for GID that are not even present in the models of mouse,” Mayer-Proschel said.
“Understanding these cellular targets of this widespread nutritional deficiency will be imperative to taking the steps needed to effect change in the way we think about maternal health. Iron is an important component of this, and the limited impact of iron supplementation after birth makes it necessary to identify alternative approaches,”
Other authors include Janine Cubello, PhD, and Robert Newell of the University of Rochester.
See also
Funding: This research was supported by the National Institute of Health’s Eunice Kennedy Shriver National Institute of Child Health and Human Development, University of Rochester Department of Environmental Health Toxicology Training Fellowship, Stem Cell Training Fellowship of New York and the Kilian J. and Caroline F. Schmitt Foundation through the pilot program at the Del Monte Institute for Neuroscience.
About this neurodevelopment research news
Author: Kelsie Smith Haydouk
Source: University of Rochester
Contact: Kelsie Smith Hayduk – University of Rochester
Picture: Image is in public domain
Original research: Access closed.
“Gestational iron deficiency affects the ratio of interneuron subtypes in postnatal cerebral cortex in mice” by Margot Mayer-Proschel et al. Development
Abstract
Gestational iron deficiency affects the ratio of interneuron subtypes in postnatal cerebral cortex in mice
Gestational iron deficiency (gID) is widespread and associated with an increased risk of intellectual and developmental disabilities in affected individuals, which are often defined by a disturbed balance of excitation and inhibition (E/I) in the brain.
Using a nutritional mouse model of gID, we previously demonstrated a shift in E/I balance toward increased inhibition in the brains of gID offspring that were refractory to postnatal iron supplementation.
We thus tested whether gID affects embryonic progenitor cells destined for inhibitory interneurons. We quantified relevant cell populations when specifying embryonic inhibitory neurons and found an increase in Nkx2.1 proliferation+ interneuron progenitors in the embryonic medial ganglionic eminence at E14 that was associated with increased Shh signaling in gID animals at E12.
When we quantified the number of mature inhibitory interneurons known to originate from the MGE, we found persistent disruption of differentiated interneuron subtypes in early adulthood.
Our data identify a cellular target that links gID to disruption of cortical interneurons that play a major role in establishing E/I balance.