In a study published in the journal Development, Northwestern Medicine scientists identified one of the molecular mechanisms responsible for the pathological variability seen in holoprosencephaly (HPE), a congenital brain malformation resulting in a range of developmental defects in the structure and function of the brain.
HPE is a rare disorder involving the incomplete division of the forebrain into two hemispheres while a fetus is still developing. HPE is caused by mutations in genes that transmit information to embryonic cells responsible for cell differentiation via the Sonic Hedgehog signaling pathway (SHH).
“HPE is characterized by its very variable range of severity, even in patients with the same mutations,” explained study senior author Guillermo Oliver, PhD, Thomas D. Spies Professor of Lymphatic Metabolism and director of the Center for Vascular and Developmental Biology at the Feinberg Cardiovascular Research Institute.
“Our paper provides conclusive evidence showing that different dosages of the transcription factor Six3 are responsible for the different types of holoprosencephaly, ranging from the very mild to the very severe cyclopic phenotype,” said Oliver, also a professor of Medicine in the Division of Nephrology.
Using novel mouse models, the scientists demonstrated that the semilobar phenotype — a partially incomplete forebrain division — is caused by the highly decreased expression of SHH in the diencephalon, a brain area that includes structures such as the thalamus and hypothalamus.
By contrast, in the alobar phenotype — the most severe form of HPE — the authors found that the developmental defects were due to abnormally decreased expression of the transcription factor Foxg1 at early developmental stages.
Moreover, the study indicates that Six3 directly regulates the expression of Foxg1, a key gene that regulates embryonic forebrain development.
“Amongst other functions, Foxg1 inhibits progenitor differentiation and regulates the expression of FGF8, a key morphogen regulating telencephalon patterning,” said Sandra Acosta, a postdoctoral fellow in Oliver’s lab and one of the first authors of the manuscript. “Thus, understanding how Foxg1 is regulated at different stages is crucial to understand the milestones of forebrain development.”
Understanding the molecular mechanisms behind the variability of HPE is the first step toward a better understanding on how gene dosage impact phenotypic variability in a range of human that could eventually lead to clinical applications, according to the authors.
“Often, parents show very mild symptoms of HPE, like cleft palate, but their carried mutation can cause more severe disorders in their offspring,” said Oliver. “Understanding that changes in the expression levels of genes implicated in HPE can vary from patient to patient might help increasing the awareness that some genetic test might be relevant in patients with mild symptoms.”
HyeaJin Gil, a postdoctoral fellow in Oliver’s lab, was also a study author.
The research was funded by US National Institutes of Health (NIH) grant EY12162.