Bcl11b/Ctip2 Controls the Differentiation of Vomeronasal Sensory Neurons in Mice

Abstract

The transcription factor Bcl11b/Ctip2 plays critical roles in the development of several systems and organs, including the immune system, central nervous system, skin and teeth. Here, we show that Bcl11b/Ctip2 is highly expressed in the developing vomeronasal system in mice and is required for its proper development. Bcl11b/Ctip2 is expressed in post-mitotic vomeronasal sensory neurons (VSNs) in the vomeronasal epithelium as well as projection neurons and GABAergic interneurons in the accessory olfactory bulb (AOB). In the absence of Bcl11b, these neurons are born in the correct number, but VSNs selectively die by apoptosis. The critical role of Bcl11b in vomeronasal system development is demonstrated by the abnormal phenotypes of Bcl11b-deficient mice: disorganization of layer formation of the AOB, impaired axonal projections of VSNs, a significant reduction in the expression of vomeronasal receptor genes, and defective mature differentiation of VSNs. VSNs can be classified into two major types of neurons, vomeronasal 1 receptor (V1r)/Gαi2-positive and vomeronasal 2 receptor (V2r)/Gαo-positive VSNs. We found that all Gαi2-positive cells co-expressed Gαo during embryogenesis. This co-expression is also observed in newly differentiated neurons in the adult VNE. Interestingly, loss of Bcl11b function resulted in an increased number of V1r/Gαi2-type VSNs and a decreased number of V2r/Gαo-type VSNs, suggesting that Bcl11b regulates the fate choice between these two VSN types. These results indicate that Bcl11b/Ctip2 is an essential regulator of the differentiation and dichotomy of VSNs.

Coordinated Regulation of Transcription Factor Bcl11b Activity in Thymocytes by the Mitogen-activated Protein Kinase (MAPK) Pathways and Protein Sumoylation

“…Disruption of the Bcl11b locus in mice results in defective neuronal (20,21), skin (22), craniofacial (23), and T-cell (20, 24 -26) development. Disruption of the human BCL11B locus has been associated with T-cell malignancies (27)(28)(29), suggesting that the protein acts as a tumor suppressor in T-cells (30).…”

Molecular Switches in the Development and Fate Specification of Vomeronasal Neurons: Figure 1.

“…In a recent article published in The Journal of Neuroscience, however, Enomoto et al (2011) showed that Bcl11b/Ctip2, a zinc finger transcription factor involved in regulating corticofugal fate of deep-layered neocortical neurons , is crucial for maturation and fate determination of vomeronasal neurons, for establishing axonal projections to the AOB, and for correct layering of intrinsic AOB neurons.…”

“…By analyzing gene expression at different developmental stages, Enomoto et al (2011) identify a sequence of events that occur during vomeronasal neuron maturation. They found that during embryogenesis, Bcl11b/Ctip2 is expressed in most terminal differentiating/immature vomeronasal neurons, whereas in adults, its expression becomes restricted to the neurogenic niches of the marginal regions of the VNO.…”

“…To further investigate the role of Bcl11b/ Ctip2 during vomeronasal neuron development, Enomoto et al (2011) knocked out Bcl11b/Ctip2 and compared the expression of several markers of neuronal developmental stages in mutant and wild-type animals. In Bcl11b/Ctip2 Ϫ/Ϫ mice, cell proliferation proceeded normally but differentiation was arrested in postmitotic neurons (Enomoto et al, 2011, their Fig.…”

“…Given the regulatory nature of Bcl11b/ Ctip2 as a transcription factor, Enomoto et al (2011) used DNA microarrays to identify genes whose expression was affected in Bcl11b/Ctip2 Ϫ/Ϫ mice. Of several genes that showed altered expression levels in knock-out mice, two were of particular interest because they are exclusively expressed at either apical or basal subpopulations: Meis2 labeled apical vomeronasal neurons and was upregulated in Bcl11b/Ctip2 Ϫ/Ϫ mice, and Tcfap2e was expressed in basal neurons and was downregulated in Bcl11b/Ctip2 Ϫ/Ϫ mice (Fig.…”