Stories about: Maria Lehtinen

Gene active before birth regulates brain folding, speech motor development

SCN3A, linked to polymicrogyria, regulates speech motor development

A handful of families from around the world with a rare brain malformation called polymicrogyria have led scientists to discover a new gene that helps us speak and swallow.

The gene, SCN3A, is turned “on” primarily during fetal brain development. When it’s mutated, a language area of the brain known as the perisylvian cortex develops multiple abnormally small folds, appearing bumpy. People with polymicrogyria in this region often have impaired oral motor development, including difficulties with swallowing, tongue movement and articulating words — especially if the polymicrogyria affects both sides of the brain.

The new study, published today in Neuron, ties together human genetics, measurements of electrical currents generated by neurons, studies of ferrets and more to start to connect the dots between SCN3A, the brain malformation and the oral motor impairment.

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Probing the brain’s earliest development, with a detour into rare childhood cancers

In early brain development there is an increase in ribosomes, contained in these nucleoli
Nucleoli, the structures in the cell nucleus that manufacture ribosomes, are enlarged in very early brain development, indicating an increase in ribosome production. Here, a 3D reconstruction of individual nucleoli. (Kevin Chau, Boston Children’s Hospital)

In our early days as embryos, before we had brains, we had a neural fold, bathed in amniotic fluid. Sometime in the early-to-mid first trimester, the fold closed to form a tube, capturing some of the fluid inside as cerebrospinal fluid. Only then did our brains begin to form.

In 2015, a team led by Maria Lehtinen, PhD, Kevin Chau, PhD and Hanno Steen, PhD, at Boston Children’s Hospital, showed that the profile of proteins in the fluid changes during this time. They further showed that these proteins “talk” to the neural stem cells that form the brain.

In new research just published in the online journal eLife, Lehtinen and Chau shed more light on this little-known early stage of brain development.

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How amniotic and cerebrospinal fluids talk to the developing brain: proteomics

proteomics amniotic fluid cerebrospinal fluid brain development
Counterclockwise, from bottom left: In the earliest stage of nervous system development, the amniotic fluid is rich with proteins, shown as dots, that communicate with neural stem cells. As the neural tube closes and the brain takes shape, the proteins become fewer and less complex. (Hillary Mullan, Boston Children’s Hospital)

When we were developing in the womb, we were immersed in amniotic fluid. As our nervous systems formed, some of this fluid was trapped inside the neural tube, forming the cerebrospinal fluid that bathes our brains.

In the past, these fluids have been seen as a “cushion” or a place to dump waste products. But new research suggests that they actively participate in nervous system development.

Publishing this week in Developmental Cell, researchers led by Maria Lehtinen, PhD, and Kevin Chau in the Department of Pathology at Boston Children’s Hospital show that amniotic fluid and cerebrospinal fluid (CSF) contain rich portfolios of proteins that tell neural stem cells what to do — how to divide and what kinds of cells to make. They also show that the messages change in different phases of development.

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Brain juice and stem cells: Revisiting an ancient view of cerebrospinal fluid

Christopher Walsh, MD, PhD, is chief of Genetics and a Howard Hughes Medical Institute Investigator at Children’s Hospital Boston, where his research focuses on genes that regulate the development and function of the human cerebral cortex. These genes are vital to normal development of the cortex, and many appear to have been altered evolutionarily to allow the unique aspects of the brain that underlie human cognitive abilities. Mutations in these genes are known to cause autism and epilepsy, as well as intellectual disabilities and other learning disorders.

Illustration of the pain pathway in René Descartes’ Traite de l’homme, 1664. The long fiber running from the foot to the head is pulled by the heat and releases a fluid that makes the muscles contract. (Wikimedia Commons)

In the second century, the Greek physician Galen proposed that the fluid in the brain provided energy for the entire body, theorizing that an external spirit (pneuma) from the lungs was transported to the heart, where, combined with blood, it would give rise to the vital spirit. Carried by the blood, the vital spirit was then thought to be transformed into an animal spirit before entering the cavities of the brain, then traveling through the nerves, “as sunshine passes through the air or water,” to energize the entire physical being.

In this view, the brain itself was a mere holder of the fluid. Our neuroanatomical term “thalamus,” referring to part of the brain stem, comes from the Greek word for “chamber,” implying that the brain was mainly important as a holder for CSF. The philosopher Descartes (1596-1650) thought that the brain was a pump that moved the fluid around to do the brain’s work, such as making a muscle contract. Seventeenth century Swedish scientist Emanuel Swedenborg referred to the CSF as a “spirituous lymph” and a “highly gifted juice.”

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