The Foundations and Futures of PRDM16


prdm16 acts as a transcription coregulator that controls the development of brown adipocytes in brown adipose tissues of the body and brain. Previously, this coregulator was believed to be present only in brown adipose tissue, but more recent studies have shown that PRDM16 is highly expressed in subcutaneous white adipose tissue as well.

Backtracking slightly here for the sake of terminology: what is adipose tissue? There are two forms of adipose tissue which when explained like this, may well ring a few bells. Brown adipose tissue (BAT) or brown fat makes up the adipose organ together, thus making it a "lean fat". White adipose tissue in contrast is white and is needed as a form of insulation upon the body and to build form on the human skeleton. For some, losing WAT is a good thing. But WAT is needed and present on all mammals in order to maintain proper bodily function and to act as an energy preservance site.

The function of PRDM16

The protein encoded by this gene is a zinc finger transcription factor. PRDM16 controls the cell fate between muscle and brown fat cells. Thus, a loss of PRDM16 from brown fat precursors causes a loss of brown fat characteristics and promotes muscle differentiation. Note now and for the forseeable future of this presentation is that the human brain is composed dominantly of fat.

The ingredients of the brain

Brains are made of soft tissue, which includes gray and white matter, containing the nerve cells, non-neuronal cells (which help to maintain neurons and brain health), and small blood vessels. They have a high water content as well as a large amount (nearly 60 percent) of fat

Weighing in at three pounds, on average, this spongy mass of fat and protein is made up of two overarching types of cells—called glia and neurons—and it contains many billions of each. Neurons are notable for their branch-like projections called axons and dendrites, which gather and transmit electrochemical signals. Different forms of glial cells are what provide physical protection to neurons and help keep them, and the brain, healthy.

Together, this complex network of cells gives rise to every aspect of our shared humanity. We could not breathe, play, love, or remember without the brain.

what makes prmd16 so profound in brain function ?

Prdm16 has been found to be required in neural stem/progenitor cells for the expression of Foxj1, a transcription factor that promotes ependymal cell differentiation. These studies show that Prdm16 is required for adult neural stem cell maintenance and neurogenesis as well as the formation of ependymal cells. Prdm16 is also required for adult stem cell function. Here we demonstrate that Prdm16 is required for neural stem cell maintenance and neurogenesis in the adult lateral ventricle subventricular zone and dentate gyrus. We also discovered that Prdm16 is required for the formation of ciliated ependymal cells in the lateral ventricle. Conditional Prdm16 deletion during fetal development using Nestin-Cre prevented the formation of ependymal cells, disrupting cerebrospinal fluid flow and causing hydrocephalus. Postnatal Prdm16 deletion using Nestin-CreERT2 did not cause hydrocephalus or prevent the formation of ciliated ependymal cells but caused defects in their differentiation. Prdm16 was required in neural stem/progenitor cells for the expression of Foxj1, a transcription factor that promotes ependymal cell differentiation. These studies show that Prdm16 is required for adult neural stem cell maintenance and neurogenesis as well as the formation of ependymal cells.

keyword check in

neurogenesis

hydrocephalus

ependymal cells

dentate gyrus

neocortex

developing the neocortex

Prdm16 is crucial for progression of the multipolar phase during neural differentiation of the developing neocortex. The precise control of neuronal migration and morphological changes during differentiation is essential for neocortical development. We hypothesized that the transition of progenitors through progressive stages of differentiation involves dynamic changes in levels of mitochondrial reactive oxygen species (mtROS), depending on cell requirements. We found that progenitors had higher levels of mtROS, but that these levels were significantly decreased with differentiation. The Prdm16 gene was identified as a candidate modulator of mtROS using microarray analysis, and was specifically expressed by progenitors in the ventricular zone. However, Prdm16 expression declined during the transition into NeuroD1-positive multipolar cells. Subsequently, repression of Prdm16 expression by NeuroD1 on the periphery of ventricular zone was crucial for appropriate progression of the multipolar phase and was required for normal cellular development. Furthermore, time-lapse imaging experiments revealed abnormal migration and morphological changes in Prdm16-overexpressing and -knockdown cells. Reporter assays and mtROS determinations demonstrated that PGC1α is a major downstream effector of Prdm16 and NeuroD1, and is required for regulation of the multipolar phase and characteristic modes of migration. Taken together, these data suggest that Prdm16 plays an important role in dynamic cellular redox changes in developing neocortex during neural differentiation.

the future of prmd16 in psychological aspects

The cerebral cortex—the brain's epicenter of high-level cognitive functions, such as memory formation, attention, thought, language and consciousness—has fascinated neuroscientists for centuries. Scientists have long known that this "command center" is organized into six distinct regions, or layers, but how this complex organization arises during development has remained largely a mystery. But it is the uncovering of the true facets behind Prmd16 that are providing the scientific community with tantalising new clues into the development of provides some tantalizing new clues into the development of the mammalian cerebral cortex.

If what we have unveiled thus far in our discoveries of prmd16 are able to be replicated and provide us with more substantial, less anomalous results, there is nothimg preventing us from a future ability to quite literally reshape our our understanding of a range of neurodevelopmental disorders.

We know that previous research has indicated that this protein helps maintain the integrity of neural stem cells—the cells that produce neurons—and help their progeny become neurons throughout development. But with further observations, we've noticed how the gene is active across all mammal species—a conservation that underscores the gene's importance during neural development across multiple organisms. Mostc critically of all, this gene is only active in neural stem cells, and is not active in the neurons that they subsequently make.

To elucidate the gene's role in the brain, researchers have created animal models in which the gene's activity was turned off. As the brains of these animals developed, their cortices grew to the same size as those in animals with normally active PRDM16. However, the of the cortices in animals with inactive PRDM16 was significantly altered presented to us that the neurons normally located in outer layers did not find their path and remained "stuck" in deeper layers. What does this tell us?

This finding suggests that the migration of neural cells from where they're 'born' in the brain to where they ultimately end up is impaired when PRDM16 isn't working. It clearly indicates that neurons of animals whose brains lacked PRDM16 couldn't find the right positions, resulting in inappropriate cortical architecture. But why and how exactly did removing PRDM16 cause such misarranged structure and improper neuronal maturation?

Previous research had already shown that this protein latches onto many sites across the entire genome of cells, affecting the expression of many genes by chemically modifying the structure of their DNA without changing the DNA sequence itself. When the researchers compared gene activity in the neureal progenitor cells of animals with PRDM16-deficient brains and those with normal levels of the protein, they found that removing PRDM16 affected more than 1,000 other genes and altered their ability to produce their respective proteins. An even closer look, added Harwell, showed that PRDM16 attaches to more than 30,000 sites of the genome that are considered noncoding—meaning that they don't directly produce proteins. But these sites are critical because they coordinate the activity of genes that are involved in establishing the number and position of neurons. That regulation appears to be passed down from progenitor to progeny, Harwell explained, affecting cells downstream of those in which PRDM16 activity is absent. In other words, only cortical neurons that have the right stem-cell lineage or pedigree are able to reach their final position in the cerebral cortex.

One of these genes directly regulated by PRDM16 known as Pdzrn3, appears to be a key regulator of the ultimate organization of the brain. The researchers showed that removing PRDM16 boosted expression of Pdzrn3 in newly produced neurons, which reduced the ability of these cells to migrate to the brain's outer layers. When the researchers reduced Pdzrn3 to normal levels, migration reverted to normal too.

To make sure this effect stemmed from PRDM16's ability to modify the structure of DNA to affect gene expression and wad not another effect of this protein, the researchers removed just the section of this protein responsible for this function. They then placed this protein back into the brains of animals in which their native PRDM16 was lacking. The mutant protein was essentially nonfunctional, leading to development akin to having no PRDM16 at all.

and finally... prmd16 and craniofacial development: how early detection, feotal CRISPR technology and genetic manipulation can be harnessed to eradicate children born with a cleft

In the United States, a baby is born with a facial cleft every hour, of every day of the year! Such birth defects result from both gene mutations and environmental insults. PRDM16 is a transcription factor originally described as being aberrantly activated in specific types of leukemia's, and more recently as a master regulator of brown adipose tissue differentiation. In a study published in the April 2012 issue of Experimental Biology and Medicine, investigators have now shown that this transcription co-factor plays a critical role in development of the embryonic palate.

If we can identify the cellular and molecular processes regulated by PRDM16 is an important step toward elucidating the underlying mechanisms important for normal embryonic development of the head and face. Thus far, over 100 genes, whose promoters were bound by PRDM16 were identified. These genes were found to be linked to such diverse processes as chromatin remodeling and muscle and bone development. We already know that there are multiple genes essential to muscle and bone development which are regulated by Prdm16 in cells isolated from the secondary palate of mouse embryos. This study should be of great significance in our understanding of birth defects leading to facial clefts. So with further study of this pivotal gene, we could be on the verge of greatness both genetically and psychologically.

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©2019 by Lait Mylk