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Research Interests

The research interests of the Xiang laboratory center on understanding the molecular mechanisms that govern the determination and differentiation of the highly specialized sensory cells and neurons. The lab employs a variety of molecular genetic approaches to identify and study transcription and other regulatory factors that are required for programming development of the retina, inner ear, spinal cord, and other CNS areas. A major focus is to develop animal models to study roles of these regulatory genes during normal sensorineural development, as well as to elucidate how mutations in these genes cause sensorineural disorders such as blindness and deafness. By gene targeting and overexpression studies, we have thus far identified Foxn4, Barhl1/2 and Brn3a/3b/3c as crucial regulatory factors that are required for fate commitment, differentiation and/or survival of various sensory cells and neurons.

Role of Foxn4 in the specification of retinal cell types. During vertebrate retinogenesis, seven classes of retinal cells are specified from multipotent progenitor cells. Previous studies have shown that the Pax6 homeoprotein is required by retinal progenitors to acquire multipotency for the genesis of rod, cone, horizontal, bipolar, ganglion, and Müller cells. However, Pax6 is not required for the genesis of amacrine interneurons, raising the possibility that another intrinsic regulator may confer retinal progenitors with the potential for amacrine cell generation. In a recent study, we have investigated the role of the Foxn4 winged-helix/forkhead transcription factor during retinal development. We have found that Foxn4 is expressed during mouse retinogenesis in a subset of dividing retinal progenitors characteristic of the subset with a fate biased toward amacrine and horizontal cells. Targeted disruption of Foxn4 largely eliminates amacrine neurons and completely abolishes horizontal cells, while overexpression of Foxn4 strongly promotes an amacrine cell fate. These results indicate that Foxn4 is both necessary and sufficient for commitment to the amacrine cell fate, and is non-redundantly required for competence acquisition for the genesis of horizontal cells. Furthermore, we provide evidence that Foxn4 controls the genesis of amacrine and horizontal cells by activating the expression of Math3, NeuroD1 and Prox1, three retinogenic factors involved in the specification of amacrine or horizontal cells. Our data together suggest a model in which Foxn4 cooperates with other key retinogenic factors to mediate the multipotent differentiation of retinal progenitors and provide a molecular explanation for the generation of a subset of lineage-biased progenitor cells during retinogenesis.

Foxn4 is required for the generation of amacrine and horizontal cells during retinogenesis. Neuron 43:795-807 (2004)

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