A survey of hypothalamic phenotypes identifies molecular and behavioral consequences of MYT1L haploinsufficiency in male and female mice.

Dougherty, J. D.; Maloney, S. E.; McCullough, K. B.; Chaturvedi, S. M.; Selmanovic, D.; Chase, R.; Chen, J.; Wu, D.; Granadillo, J. L.; Kroll, K. L.

doi:10.1101/2024.11.25.625294

bioRxiv · 10.1101/2024.11.25.625294

A survey of hypothalamic phenotypes identifies molecular and behavioral consequences of MYT1L haploinsufficiency in male and female mice.

Dougherty, J. D.·Maloney, S. E.·McCullough, K. B.·Chaturvedi, S. M.·Selmanovic, D.·Chase, R.·Chen, J.·Wu, D.·Granadillo, J. L.·Kroll, K. L.

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Abstract

The transcription factor MYT1L supports proper neuronal differentiation and maturation during brain development. MYT1L haploinsufficiency results in a neurodevelopmental disorder characterized by intellectual disability, developmental delay, autism, behavioral disruptions, aggression, obesity and epilepsy. While MYT1L is expressed throughout the brain, how it supports proper neuronal function in distinct regions has not been assessed. Some features of MYT1L Neurodevelopmental Syndrome suggest disruption of hypothalamic function, such as obesity and endocrine issues, and previous research showed changes in hypothalamic neuropeptide expression following knockdown in zebrafish. Here, we leveraged our heterozygous Myt1l mutant, previously shown to recapitulate aspects of the human syndrome such as hyperactivity, social challenges, and obesity, to examine the impact of MYT1L loss on hypothalamic function. Examining the molecular profile of the MYT1L haploinsufficient hypothalamus revealed a similar scale of disruption to previously studied brain regions, yet with region-specific roles for MYT1L, including regulation of neuropeptide systems. Alterations in oxytocin and arginine vasopressin cell numbers were also found. Behaviors studied included maternal care, social group hierarchies, and aggression, all of which were unchanged. Feeding and metabolic markers were also largely unchanged in MYT1L haploinsufficient mice, yet an interaction was observed between diet and MYT1L genotype on weight gain. Our findings here suggest that gross endocrine function was not altered by MYT1L haploinsufficiency, and that key sex-specific behaviors related to proper hypothalamic function remain intact. Further study is needed to understand the functional impact of the altered hypothalamic molecular profile and changes in neuropeptide cell numbers that result from MYT1L haploinsufficiency.

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Dougherty, J. D., Maloney, S. E., McCullough, K. B., Chaturvedi, S. M., Selmanovic, D., Chase, R., Chen, J., Wu, D., Granadillo, J. L., Kroll, K. L.. 2024-11-25. A survey of hypothalamic phenotypes identifies molecular and behavioral consequences of MYT1L haploinsufficiency in male and female mice.. https://doi.org/10.1101/2024.11.25.625294

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