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Oculomotor Circuitry

Dr. Whitman’s lab is currently studying development of the brainstem circuitry controlling eye movements through transsynaptic viral tracing. They are also examining whether brainstem circuitry develops abnormally in mouse models of nystagmus.

Strabismus Genetics

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Dr. Whitman has been examining the genetics of both paralytic and nonparalytic forms of strabismus. The paralytic forms often have clear Mendelian inheritance, and, for many of them, causative genes have been identified. In the nonparalytic forms, which are much more common, there is clear heritability, but no causative genes have been identified. CFEOM3 is caused by mutations in a neuron-specific beta tubulin isotype, TUBB3. Previously reported human mutations in TUBB3 cause either CFEOM or malformations of cortical development but never both. She has reported two new mutations in the TUBB3 gene, which cause both CFEOM and malformations of cortical development, changing the previous hypothesis that these distinct phenotypes arise from distinct mechanisms. Additionally, she contributed to the Genome-Wide Association Study of nonaccommodative esotropia, where she identified a risk allele on chromosome 21, in an intron of the WRB gene. Her contribution was to show that this risk allele is differentially methylated and preferentially inherited paternally in affected individuals. Copy number variants (CNVs) are another potential source of genetic variation, and have recently been implicated in other neurological disorders, including intellectual disability and Tourette syndrome. She has examined a cohort of esotropia patients for rare CNVs and found that both deletions and duplications tend to be larger in esotropia patients than in controls. Dr. Whitman continues to enroll strabismus patients in her studies. She has identified three recurrent rare duplications that are significantly more common in esotropia patients than in controls, and are associated with specific types of esotropia (Whitman MC, Di Gioia SA, Chan WM, Gelber A, Pratt BM, Bell JL, Collins TE, Knowles JA, Armoskus C, Pato M, Pato C, Shaaban S, Staffieri S, MacKinnon S, Maconachie GDE, Elder JE, Traboulsi EI, Gottlob I, Mackey DA, Hunter DG, Engle EC. Recurrent Rare Copy Number Variants Increase Risk for Esotropia. Invest Ophthalmol Vis Sci. 2020 08 03; 61(10):22. PMID: 32780866).

Oculomotor Axon Guidance

Another focus of the Whitman Lab is on development and axon guidance of the oculomotor nerve. Together with a medical student Dr. Whitman was mentoring, she showed that, in the absence of extraocular muscles, ocular motor nerves reach the orbit appropriately but then fail to form terminal branches within the orbit and have increased cell death. This indicates that initial axon guidance cues come from the mesenchyme, not the muscles, but muscle-derived cues are also necessary for terminal branching decisions and provide trophic support to the developing neurons. She developed a new ex vivo oculomotor slice technique and, using this technique, identified the chemokine receptor CXCR4 as regulating ventral exit of axons from the midbrain. In vivo, she has shown that, in the absence of CXCR4 or its ligand CXCL12, oculomotor axons project dorsally rather than ventrally from the midbrain, and there is aberrant innervation from the motor trigeminal nerve to extraocular muscles—a model of oculomotor synkinesis and an indication that uninnervated extraocular muscles potentially release signaling cues that attract other motor axons. She then showed that, in humans, a variant in the related receptor ACKR3 (CXCR7) leads to oculomotor synkinesis. This indicates that ACKR3 regulates CXCL12 levels in the midbrain, the human mutation decreases its binding affinity for CXCL12, and loss of Ackr3 in mice leads to misrouting of the ocular motor nerves and oculomotor synkinesis.