A new study provides an explanation for why certain leukemia patients do not respond to therapy
3D confocal laser microscopy showing the expression of MN1 (magenta) in embryos of four different vertebrate species using HCR in situ hybridization. From left to right: mouse, chicken, zebrafish and small-spotted catshark.
© Elio Escamilla
To the Point
- Ancient origin: MN1 is an ancient gene that underwent structural changes at the origin of vertebrates
- Integration: MN1 integrated to ancient molecular machinery and fuelled the origin of novel developmental program
- Brain-skull connection: MN1 controls both the brain patterning and skull formation, representing the long-sought genetic and mechanistic basis of brain and skull co-development and co-evolution
- Medical relevance: understanding the MN1 function allows to comprehend congenital syndromes and leukemia therapy resistance
The brain and skull are a biological duo-growing and forming together in perfect coordination during early development. This close partnership isn't just a coincidence. Over millions of years of evolution, the brain and skull have adapted together, shaping each other to ensure protection, function, and survival. Scientists have long observed this connection, but the genetic instructions that guide this synchronized growth-and how it evolved-have remained largely unknown. Until now.
Researchers at the Max Planck Institute for Evolutionary Biology led by Markéta Kaucká have discovered that MN1, a gene originally associated with brain tumours and leukaemia, actually evolved hundreds of millions of years ago in primitive invertebrate animals. At the onset of vertebrates, animals possessing more complex brain and also the skull, the gene underwent structural changes and became indispensable for vertebrate development.
A Gene from the Dawn of Deuterostomes
3D confocal laser microscopy showing the expression of Mn1 (magenta) in a mouse embryo at embryonic day 10 using HCR in situ hybridization.
© Elio Escamilla
The researchers traced MN1's ancestry back to primitive invertebrate animals. Though structurally distinct in invertebrates, a core MN1 sequence was preserved during vertebrate evolution. In jawed vertebrates, MN1gained a new short exon encoding a C-terminal domain that became essential for its function in brain development and skull formation.
The team interested in the evolution of developmental processes found that MN1 helps to pattern embryonic brain during early development and, in turn, controls the formation of the cranial bones. Without MN1, brain segmentation is impaired, cranial nerves form abnormally, and bones in the skull develop incorrectly-mirroring defects seen in human syndromes like cleft palate, skull deformities and neurodevelopmental delays.
Strikingly, these issues echo the previously observed effects of altering retinoic acid levels. The team showed that MN1 controls the levels of retinoic acid, a vital molecule in embryo development, and expression patterns of Hox genes, which act like a blueprint guiding the body plan of an embryo along the head-to-tail axis, linking MN1 function to a known and ancient signaling pathways.
Keeping growth in sync
This discovery thus sheds light on how vertebrates evolved the two defining features-brain and skull-and how a single gene helps keep their formation and growth in sync. The research also illuminates broader concept-how gene evolution allows their integration into ancient molecular systems and drive the innovations and macroevolutionary transitions.
The findings additionally offer explanation of why certain leukemia patients don't respond well to retinoic acid therapy. Patients with high MN1 levels show treatment resistance, likely due to the fact that MN1 enables quick degradation of the drug, preventing it from action. The study also draws connections to numerous human disorders, where truncations and mutations in MN1 were linked to neurodevelopmental and craniofacial syndromes.
