Eseng Lai

Winged helix transcription factor BF-1 is essential for the development of the cerebral hemispheres

We generated mice with a null mutation of the forebrain-restricted transcription factor BF-1 to examine its function in brain development. Heterozygous animals have an apparently normal phenotype. Homozygous null BF-1 mutants die at birth and have a dramatic reduction in the size of the cerebral hemispheres. The development of the ventral telencephalon is more severely affected than that of the dorsal telencephalon. Telencephalic neuroepithelial cells are specified in the BF-1 mutant, but their proliferation is reduced. Dorsal telencephalic neuroepithelial cells also differentiate prematurely, leading to early depletion of the progenitor population. These results suggest that BF-1 controls the morphogenesis of the telencephalon by regulating the rate of neuroepithelial cell proliferation and the timing of neuronal differentiation.

Foxg1 is required for morphogenesis and histogenesis of the mammalian inner ear

The forkhead genes are involved in patterning, morphogenesis, cell fate determination, and proliferation. Several Fox genes (Foxi1, Foxg1) are expressed in the developing otocyst of both zebrafish and mammals. We show that Foxg1 is expressed in most cell types of the inner ear of the adult mouse and that Foxg1 mutants have both morphological and histological defects in the inner ear. These mice have a shortened cochlea with multiple rows of hair cells and supporting cells. Additionally, they demonstrate striking abnormalities in cochlear and vestibular innervation, including loss of all crista neurons and numerous fibers that overshoot the organ of Corti. Closer examination shows that some anterior crista fibers exist in late embryos. Tracing these fibers shows that they do not project to the brain but, instead, to the cochlea. Finally, these mice completely lack a horizontal crista, although a horizontal canal forms but comes off the anterior ampulla. Anterior and posterior cristae, ampullae, and canals are reduced to varying degrees, particularly in combination with Fgf10 heterozygosity. Compounding Fgf10 heterozygotic effects suggest an additive effect of Fgf10 on Foxg1, possibly mediated through bone morphogenetic protein regulation. We show that sensory epithelia formation and canal development are linked in the anterior and posterior canal systems. Much of the Foxg1 phenotype can be explained by the participation of the protein binding domain in the delta/notch/hes signaling pathway. Additional Foxg1 effects may be mediated by the forkhead DNA binding domain. Developmental Dynamics 235:2470–2482, 2006.

Domains of Regulatory Gene Expression and the Developing Optic Chiasm: Correspondence With Retinal Axon Paths and Candidate Signaling Cells

In mammals, some axons from each retina cross at the optic chiasm, whereas others do not. Although several loci have been identified within the chiasmatic region that appear to provide guidance cues to the retinal axons, the underlying molecular mechanisms that regulate this process are poorly understood. Here we investigate whether the earliest retinal axon trajectories and a cellular population (CD44 and stage‐specific embryonic antigen 1 [SSEA] neurons), previously implicated in directing axon growth in the developing chiasm (reviewed in Mason and Sretavan [1997] Curr. Op. Neurobiol. 7:647–653), correlate with the expression patterns of several regulatory genes (BF‐1, BF‐2, Dlx‐2, Nkx‐2.1, Nkx‐2.2, and Shh). These studies demonstrate that gene expression patterns in the chiasmatic region reflect the longitudinal subdivisions of the forebrain in that axon tracts in this region generally are aligned parallel to these subdivisions. Moreover, zones defined by overlapping domains of regulatory gene expression coincide with sites implicated in providing guidance information for retinal axon growth in the developing optic chiasm. Together, these data support the hypothesis that molecularly distinct, longitudinally aligned domains in the forebrain regulate the pattern of retinal axon projections in the developing hypothalamus. J. Comp. Neurol. 1999:346–358, 1999.

Dynamics of placodal lineage development revealed by targeted transgene expression

Examination of the expression pattern of the winged‐helix transcription factor BF‐1 outside of the neural tube in mouse embryos suggests that BF‐1 is restricted to a population of cells that gives rise to the ectodermal placodes and their derivatives. Within the sensory cranial nerve ganglia, the expression of BF‐1 distinguishes cells that arise from the placodes from those derived from the neural crest. Expression of a lacZ transgene targeted to the BF‐1 locus was used to follow the placodal lineage during mouse development. Analysis of placodal development in mice with a targeted deletion of BF‐1 reveals that, although BF‐1 is required for proliferation of the cells arising from the nasal placode, it is not required for the proliferation, survival, or both, of placode‐derived cells in the sensory cranial nerve ganglia. Dev Dyn 1999;215:332–343.

TWH Regulates the Development of Subsets of Spinal Cord Neurons

Thymocyte winged helix (TWH) is a putative transcription factor expressed in the developing neural tube. At midgestation, TWH expression identifies subsets of spinal cord motor neurons and interneurons. TWH-expressing motor neurons were restricted to specific spinal cord levels, distinguishing motor neurons at lumbar from those at cervical levels. To understand the developmental role of TWH, we replaced the TWH gene with the lacZ reporter gene and generated mice with a homozygous disruption of the TWH gene. TWH(-/-) mutant mice had increased perinatal mortality, retarded postnatal growth, and motor weakness. The TWH(-/-) mutation resulted in alterations in the sizes and position of different neuronal populations. Our results demonstrate that TWH plays a critical role in neuronal development and suggest that TWH regulates the early differentiation of neural progenitors.

Foxg1 is required for proper separation and formation of sensory cristae during inner ear development

The vestibular portion of the inner ear, the three semicircular canals and their sensory cristae, is responsible for detecting angular head movements. It was proposed that sensory cristae induce formation of their non‐sensory components, the semicircular canals. Here, we analyzed the inner ears of Foxg1−/− mouse mutants, which display vestibular defects that are in conflict with the above model. In Foxg1−/− ears, the lateral canal is present without the lateral ampulla, which houses the lateral crista. Our gene expression analyses indicate that at the time when canal specification is thought to occur, the prospective lateral crista is present, which could have induced lateral canal formation prior to its demise. Our genetic fate‐mapping analyses indicate an improper separation between anterior and lateral cristae in Foxg1−/− mutants. Our data further suggest that a function of Foxg1 in the inner ear is to restrict sensory fate. Developmental Dynamics 238:2725–2734, 2009.