Transcriptional control of forebrain regionalisation

The thalamus is the major relay station of the brain that forwards sensory information from the periphery to higher brain centres. It can also filter and dampen input selectively, thereby regulating sleep, consciousness, pain, arousal, awareness and activity. Developmentally, the thalamus originates from the posterior forebrain (diencephalon) which is subdivided (from rostral to caudal) into the prethalamus (PTH), rostral thalamus (R-TH), caudal thalamus (C-TH) and pretectum (PTE). PTH, R-TH and C-TH give rise to the approximately 50 nuclei of the thalamus proper whereas the nuclei originating from the PTE are traditionally assigned to the midbrain. PTH and R-TH are separated by a transverse stripe of cells called the zona limitans intrathalamica (ZLI) that functions as an organiser by secreting SHH. We showed previously that high levels of SHH immediately posterior to the ZLI induce the GABAergic (inhibitory) progenitors of the R-TH whereas lower levels further away induce the glutamatergic (excitatory) neurons of the C-TH (Kiecker & Lumsden, 2004; Robertshaw et al., 2013).

Although cells on either side of the ZLI transduce the SHH signal, their response to this signal is strikingly different: the GABAergic and glutamatergic neurons of the R-TH and C-TH are induced posterior to the ZLI, whereas a different transcriptional response is elicited in the PTH anterior to the ZLI. We recently demonstrated that this differential competence is mediated by IRX3 which is expressed on the posterior, but not on the anterior side of the ZLI (Kiecker & Lumsden, 2004; Robertshaw et al., 2013). We are exploiting this experimental system in order to investigate the molecular basis for differential competence. Currently, we are testing the following three (not necessarily mutually exclusive) hypotheses: (i) IRX3 regulates differential competence by modifying the gene regulatory network of the SHH response; (ii) IRX3 modulates differential competence by regulating other signalling pathways (such as the WNT pathway); (iii) IRX3 establishes differential competence through epigenetic regulation at the chromatin level. IRX3 is not only expressed in the developing CNS, but also in other regions of the embryo in proximity to sources of SHH signalling—for example in the developing limb bud. By comparing the interaction of IRX3 with SHH in these very different embryonic tissues (collaboration with Prof Malcolm Logan), we hope to obtain a better general understanding of different cellular responses to SHH, a signal that is of great importance not only in embryonic development, but also in adult homeostasis.