Tuesday, December 11, 2012
12:00 pm
Broad 100

Dev Bio SuperGroup Meeting

Long Li, Transcriptional regulation of T cell lineage commitment, Rothenberg Lab- Biology, Caltech
Ankur Saxena, Sox10-dependent neural crest origin for olfactory microvillous neurons", Bronner Lab - Biology, Caltech

Transcriptional Regulation of T cell Lineage Commitment - Long Li
T cell lineage commitment is a process to silence the alternative lineage developmental potentials and selfrenewal
in T cell precursors. It safeguards T cell identity and prevents oncogenic transformation of early T
cells. We and others have identified Bcl11b as a major regulator of the T cell lineage commitment
checkpoint. When Bcl11b-deficient HSCs were cultured on OP9DL1, the development of the cells was
blocked at DN2a, the stage right before the commitment checkpoint. Prolonged culture of Bcl11b-deficient
DN2a cells showed that in the absence of Bcl11b, the cells retain self-renewal capacity. These cells also had
great developmental potentials to trans-differentiate into NK and myeloid cells under certain conditions.
RNA-seq and qPCR have identified that many genes are de-regulated in Bcl11b-deficient DN2a cells,
including the genes associated with stem cell regulatory program and NK development potential. Therefore,
Bcl11b regulates the T-lineage commitment by repressing self-renewal, NK and myeloid developmental
potentials of the early T cells. However, the transcription factor that excludes B-lineage developmental
potential in early T cells has remained unknown. GATA-3 has been a famous regulator of T-lineage
specification and survival/proliferation. Here, we identified a new role of GATA-3 in early T cell development
as being a major regulator of the B-lineage-exclusion function of T-lineage commitment. Normally, DN2 T
cells have completed lost B cell potential, and when they are cultured under conditions that support B/NK cell
development, they generate NK cells. However, when GATA-3-deficient DN2 T cells were sorted and
cultured under these conditions for about 10 days, CD19+B220+ cells were consistently developed from the
culture. The results were also confirmed by colony assays. These CD19+ cells developed from GATA-3-
deficient DN2 T cells expressed B-lineage master regulators EBF-1 and Pax5 at levels comparable to spleen
B cells. Further analysis showed that these T-to-B cells also expressed significant amount of mRNA from
rearranged TCRγ and δ loci, which indicates that the cells developed from T-lineage cells. The results
provided the first clear evidence showing that T cells at a stage normally associated with commitment gain
B-lineage potential upon Gata3 deletion. Therefore, we conclude that GATA-3 and Bcl11b collectively
function as complementary regulators of the T cell lineage commitment to lock down T cell fate in the
otherwise multipotent T cell precursors.

Sox10-Dependent Neural Crest Origin for Olfactory Microvillous Neurons - Ankur Saxena
The sense of smell in vertebrates is detected by specialized sensory neurons derived from the peripheral
nervous system. Classically, it has been presumed that the olfactory placode forms all olfactory sensory
neurons. In contrast, we show that the cranial neural crest is the primary source of microvillous sensory
neurons within the olfactory epithelium. Using photoconversion-based fate mapping and live cell tracking
coupled with laser ablation in zebrafish embryos, we followed neural crest precursors as they migrated from
the neural tube to the nasal cavity. A subset that coexpressed Sox10 protein and a neurogenin1 reporter
ingressed into the olfactory epithelium and differentiated into microvillous sensory neurons. Timed loss-offunction
analysis revealed a critical role for Sox10 in microvillous neurogenesis. Taken together, these
findings directly demonstrate a heretofore unknown contribution of the cranial neural crest to olfactory
sensory neurons and provide important insights into the assembly of the nascent olfactory system

Contact Julie Boucher jboucher@caltech.edu at 395-4952
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