The specification of neuronal cell types in the developing neural tube is orchestrated by signaling centers. However, how patterned territories of the central nervous system (CNS) are organized into structures with appropriate size and shape is still unclear. We report that in the absence of the mouse transcription factor mBtd/Sp8, a posterior shift of the isthmic organizer(IsO) occurs, suggesting a crucial role for Sp8 in this process. In addition,large patches of cells ectopically expressing Fgf8, Otx2 and/or Wnt1 in the rostral hindbrain are detected in Sp8 mutant embryos. In this context, midbrain dopaminergic neurons are found posterior to the IsO. Furthermore, we provide evidence that cell proliferation in the mid-and hindbrain is tightly controlled by Sp8 activity. Our observations are consistent with a role for Sp8 in restricting Fgf8 expression at the IsO.

The specification of the different mouse pancreatic endocrine subtypes is determined by the concerted activities of transcription factors. However, the molecular mechanisms regulating endocrine fate allocation remain unclear. In the present study, we uncover the molecular consequences of the simultaneous depletion of Arx and Pax4 activity during pancreas development. Our findings reveal a so far unrecognized essential role of the paired-box-encoding Pax4 gene. Specifically, in the combined absence of Arx and Pax4 , an early-onset loss of mature α- and β-cells occurs in the endocrine pancreas, concomitantly with a virtually exclusive generation of somatostatin-producing cells. Furthermore, despite normal development of the PP-cells in the double-mutant embryos, an atypical expression of the pancreatic polypeptide (PP) hormone was observed in somatostatin-labelled cells after birth. Additional characterizations indicate that such an expression of PP was related to the onset of feeding, thereby unravelling an epigenetic control. Finally, our data provide evidence that both Arx and Pax4 act as transcriptional repressors that control the expression level of one another, thereby mediating proper endocrine fate allocation.