Primary cilia are microscopic sensory antennae that transmit extracellular signals into intracellular biochemical responses. Growing evidence indicates that primary cilia are implicated in brain development and intellectual disabilities, but the functional role of primary cilia in neurodevelopmental disorders, such as fragile X syndrome (FXS) are largely unknown. Now, researchers at the University of Texas Health Science Center at San Antonio (UT Health San Antonio), found that primary cilia are present in fewer numbers in mice born with FXS.
Their study is published in Stem Cell Reports, in a paper titled, “Primary Ciliary Deficits in the Dentate Gyrus of Fragile X Syndrome.”
Primary cilia play important roles in development and physiology, and defects of primary cilia cause a wide range of human disease symptoms, termed ciliopathies. Ciliopathy patients display a range of neurological disorders including cognitive deficits and behavioral phenotypes. Aimed at finding a link between primary cilia and neurodevelopmental disorders, the researchers used a mouse model of FXS.
FXS is a genetic disorder that causes a range of developmental problems. Affected individuals usually have delayed development of speech and language by age two. Most males with fragile X syndrome have mild to moderate intellectual disability, while about one-third of affected females are intellectually disabled. Children with fragile X syndrome may also have anxiety and hyperactive behavior, and may have attention deficit disorder (ADD).
The research team was led by Hye Young Lee, PhD, assistant professor at UT Health San Antonio. The team focused on primary cilia located in a brain structure called the dentate gyrus (DG), which is part of the hippocampus.
The dentate gyrus is the first region where all sensory modalities merge together to form unique representations and memories that bind stimuli together. The dentate gyrus serves as a nursery for newborn neurons, which depend on the primary cilia to enable their maturation.
The researchers found that the number of primary cilia was significantly reduced in the DG, but not altered in the somatosensory cortex, entorhinal cortex, and hippocampus proper in fragile X mental retardation 1 (Fmr1) KO mice compared with wild-type (WT) mice.
Lee noted that primary cilia have not previously been linked to fragile X syndrome.
“When we further investigated primary cilia in various prenatal and postnatal developmental stages, we found a significant reduction in the number of primary cilia in the DG of Fmr1 KO mice after postnatal day 14 (P14), but not in earlier postnatal ages or in embryos. Furthermore, the primary cilia loss in the DG of Fmr1 KO mice was specifically found in mature granule neurons, especially in newborn neurons differentiated from the subgranular zone (SGZ) in the DG.”
“If we get to know how the primary cilia work in the newborn neuron and how they contribute to fragile X syndrome, the next step would be to promote them,” Lee explained.
“There are drugs to do that, and they could be potential therapies for fragile X syndrome and other neurodevelopmental disorders, because there are multiple studies showing that neurodevelopmental disorders and autism can be reversed in adults,” Lee concluded.
Their findings may lead to further studies understanding the connection of cilia deficits and the brain, and may one day lead to the reversal of neurodevelopmental disorders.
