Over half of children with NF1 have some form of learning disability or issues with attention, while nearly one quarter of children with NF1 have difficulties with social interactions (autism). While many of these children are successfully treated with medication and behavior therapy, we aim to better understand these features of NF1 in order to improve treatment and patient care.
- Defining the role of the NF1 gene in normal brain development
- Developing new treatments for learning, behavioral, motor, and sleep deficits in children with NF1
Defining the role of the NF1 gene in normal brain development
The observation that children with NF1 have learning, memory and behavioral problems suggests that the NF1 gene is important in brain development and function.
To understand the role of the NF1 protein (neurofibromin) in normal brain development, Dr. David Gutmann and Dr. Corina Anastasaki are using mice and human cells. These studies are aimed at determining the mechanisms by which the NF1 gene controls the growth of progenitor cells (neural stem cells) and their differentiation into neurons, astrocytes and oligodendrocytes. The goal of these studies is to determine exactly how neurofibromin regulates normal brain development and function with an eye towards future treatments that leverage these new insights.
Wegscheid ML, Anastasaki C, Hartigan KA, Cobb OM, Papke JB, Traber JN, Morris SM, Gutmann DH. Patient-derived iPSC-cerebral organoid modeling of the 17q11.2 microdeletion syndrome establishes CRLF3 as a critical regulator of neurogenesis. Cell Rep. 2021 Jul 6;36(1):109315. doi: 10.1016/j.celrep.2021.109315. PMID: 34233200
Chen YH, Gianino SM, Gutmann DH. Neurofibromatosis-1 regulation of neural stem cell proliferation and multilineage differentiation operates through distinct RAS effector pathways. Genes Dev. 2015 Aug 15;29(16):1677-82. doi: 10.1101/gad.261677.115. Epub 2015 Aug 13. PMID: 26272820.
Brown JA, Gianino SM, Gutmann DH. Defective cAMP generation underlies the sensitivity of CNS neurons to neurofibromatosis-1 heterozygosity.J Neurosci. 2010 Apr 21;30(16):5579-89. doi: 10.1523/JNEUROSCI.3994-09.2010. PMID: 20410111.
Developing new treatments for learning, behavioral, motor and sleep deficits in children with NF1
Many children with NF1 have learning difficulties, behavioral problems (autism, attention deficit), motor delays, and sleep disturbances. In an effort to develop new treatments for these common problems, cross-disciplinary studies by Drs. Susan Maloney, Yuan Pan, and Nicole Brossier at the Washington University NF Center are leveraging Nf1 genetically-engineered mice to identify why these problems arise and how best to treat them.
Rahn RM, Weichselbaum CT, Gutmann DH, Dougherty JD, Maloney SE. Shared developmental gait disruptions across two mouse models of neurodevelopmental disorders. J Neurodev Disord. 2021 Mar 20;13(1):10. doi: 10.1186/s11689-021-09359-0. PMID: 33743598
Maloney SE, Chandler KC, Anastasaki C, Rieger MA, Gutmann DH, Dougherty JD. Characterization of early communicative behavior in mouse models of neurofibromatosis type 1. Autism Res. 2018 Jan;11(1):44-58. doi: 10.1002/aur.1853. Epub 2017 Aug 26. PMID: 28842941.
Diggs-Andrews KA, Tokuda K, Izumi Y, Zorumski CF, Wozniak DF, Gutmann DH. Dopamine deficiency underlies learning deficits in neurofibromatosis-1 mice. Ann Neurol. 2013 Feb;73(2):309-15. doi: 10.1002/ana.23793. Epub 2012 Dec 7. PMID: 23225063.