IADR Abstract Archives
Craniosynostosis-Related Molecule Nell-1 Has Distinctive Functions in Neurological Anomalies
Objectives: Craniofacial anomalies comprise diverse head and facial bone growth deformities, accompanied to which neurological disorders that are not rare. Traditionally, the associated brain damage was physically attributed to craniofacial bone deformation, although this hypothesis is not fully verified. Interestingly, a well-known osteoinductive protein, neural EGF-like 1 (Nell-1) that was first identified in the prematurely fused sutures of craniosynostosis patients, is highly expressed in the brain. Moreover, we also identified contactin-associated protein-like 4 (Cntnap4), an interneuron presynaptic membrane protein, as a novel functional receptor of Nell-1 in the craniofacial bone. Considering Cntnap4’s essential role in autism spectrum disorders (ASD) and hydrocephalus, it is important to assess the function of Nell-1 in the neurological system as well.
Methods: Comprehensive behavioral tests were performed with Nell-1 haploinsufficient (Nell-1+/6R) mice compared to their wildtype littermates. Besides, Risperidone, an antipsychotic medication, was administrated to correct the abnormal behaviors of Nell-1+/6R mice. Meanwhile, gene profiling of Nell-1+/6R and wildtype mouse hippocampus via high-throughput RNA sequencing was used to gain insight into the underlying mechanism.
Results: Nell-1+/6R mice had normal behaviors in the open field arena, rotarod, and context fear conditioning tests but demonstrated elevated sensory reactivity and sensorimotor integration in the pre-pulse inhibition test and strong repetitive behavior in the marble-burying test. Importantly, Nell-1+/6R mice displayed excessive overgrooming, severe seizure, and deficient social interaction. Additionally, RNA sequencing revealed that Nell-1 deficiency significantly altered the expression of neurological disorder-related genes. On the other hand, Risperidone administration improved Nell-1+/6R mice's behavior in marble-burying and three-chamber social interaction tests.
Conclusions: Not only has an osteogenic function, Nell-1 also tremendously affects brain functions. The current study reveals that the molecules shared by craniofacial bone and the neural system might explain, at least in some degrees, the association of craniofacial and neurological disorders and open a new avenue for therapy development.
Methods: Comprehensive behavioral tests were performed with Nell-1 haploinsufficient (Nell-1+/6R) mice compared to their wildtype littermates. Besides, Risperidone, an antipsychotic medication, was administrated to correct the abnormal behaviors of Nell-1+/6R mice. Meanwhile, gene profiling of Nell-1+/6R and wildtype mouse hippocampus via high-throughput RNA sequencing was used to gain insight into the underlying mechanism.
Results: Nell-1+/6R mice had normal behaviors in the open field arena, rotarod, and context fear conditioning tests but demonstrated elevated sensory reactivity and sensorimotor integration in the pre-pulse inhibition test and strong repetitive behavior in the marble-burying test. Importantly, Nell-1+/6R mice displayed excessive overgrooming, severe seizure, and deficient social interaction. Additionally, RNA sequencing revealed that Nell-1 deficiency significantly altered the expression of neurological disorder-related genes. On the other hand, Risperidone administration improved Nell-1+/6R mice's behavior in marble-burying and three-chamber social interaction tests.
Conclusions: Not only has an osteogenic function, Nell-1 also tremendously affects brain functions. The current study reveals that the molecules shared by craniofacial bone and the neural system might explain, at least in some degrees, the association of craniofacial and neurological disorders and open a new avenue for therapy development.