title: Pax6 regulates the formation of the habenular nuclei by controlling the temporospatial expression of Shh in the diencephalon in vertebrates.
abstract: BACKGROUND
  The habenula and the thalamus are two critical nodes in the forebrain circuitry and they connect the midbrain and the cerebral cortex in vertebrates. The habenula is derived from the epithalamus and rests dorsally to the thalamus. Both epithalamus and thalamus arise from a single diencephalon segment called prosomere (p)2. Shh is expressed in the ventral midline of the neural tube and in the mid-diencephalic organizer (MDO) at the zona limitans intrathalamica between thalamus and prethalamus. Acting as a morphogen, Shh plays an important role in regulating cell proliferation and survival in the diencephalon and thalamic patterning. The molecular regulation of the MDO Shh expression and the potential role of Shh in development of the habenula remain largely unclear.
  
  
  RESULTS
  We show that deleting paired-box and homeobox-containing gene Pax6 results in precocious and expanded expression of Shh in the prospective MDO in fish and mice, whereas gain-of-function of pax6 inhibits MDO shh expression in fish. Using gene expression and genetic fate mapping, we have characterized the expression of molecular markers that demarcate the progenitors and precursors of habenular neurons. We show that the thalamic domain is shifted dorsally and the epithalamus is missing in the alar plate of p2 in the Pax6 mutant mouse. Conversely, the epithalamus is expanded ventrally at the expense of the thalamus in mouse embryos with reduced Shh activity. Significantly, attenuating Shh signaling largely rescues the patterning of p2 and restores the epithalamus in Pax6 mouse mutants, suggesting that Shh acts downstream of Pax6 in controlling the formation of the habenula. Similar to that found in the mouse, we show that pax6 controls the formation of the epithalamus mostly via the regulation of MDO shh expression in zebrafish.
  
  
  CONCLUSIONS
  Our findings demonstrate that Pax6 has an evolutionarily conserved function in establishing the temporospatial expression of Shh in the MDO in vertebrates. Furthermore, Shh mediates Pax6 function in regulating the partition of the p2 domain into the epithalamus and thalamus.
authors: Mallika
authors: M
authors: Chatterjee
authors: Qiuxia
authors: Q
authors: Guo
authors: Sabrina
authors: S
authors: Weber
authors: Department of Genetics and Developmental Biology, University of Connecticut Health Center, 400 Farmington Avenue, Farmington, CT, 06030-6403, USA. steffen.scholpp@kit.edu.
authors: Steffen
authors: S
authors: Scholpp
authors: James Yh
authors: JY
authors: Li
mesh_terms: D000818:Animals; D015415:Biomarkers / Q000378:metabolism; D019521:Body Patterning / Q000235:genetics; D004622:Embryo, Mammalian / Q000166:cytology / Q000378:metabolism; D004625:Embryo, Nonmammalian / Q000166:cytology / Q000378:metabolism; D005136:Eye Proteins / Q000378:metabolism*; D018507:Gene Expression Regulation, Developmental; D019262:Habenula / Q000166:cytology / Q000196:embryology* / Q000378:metabolism*; D053823:Hedgehog Proteins / Q000235:genetics* / Q000378:metabolism; D018398:Homeodomain Proteins / Q000378:metabolism*; D051379:Mice; D020897:Organizers, Embryonic / Q000166:cytology / Q000196:embryology; D000071841:PAX6 Transcription Factor; D051761:Paired Box Transcription Factors / Q000378:metabolism*; D011485:Protein Binding; D012097:Repressor Proteins / Q000378:metabolism*; D015398:Signal Transduction / Q000235:genetics; D013234:Stem Cells / Q000166:cytology / Q000378:metabolism; D013788:Thalamus / Q000166:cytology / Q000196:embryology; D014157:Transcription Factors / Q000378:metabolism; D014714:Vertebrates / Q000196:embryology* / Q000235:genetics; D015027:Zebrafish / Q000196:embryology / Q000378:metabolism; D029961:Zebrafish Proteins / Q000235:genetics* / Q000378:metabolism
chemical_list: D015415:Biomarkers; D005136:Eye Proteins; D053823:Hedgehog Proteins; D018398:Homeodomain Proteins; D000071841:PAX6 Transcription Factor; D051761:Paired Box Transcription Factors; C000605732:Pax6 protein, mouse; D012097:Repressor Proteins; C465570:Shh protein, mouse; C524053:Shha protein, zebrafish; D014157:Transcription Factors; D029961:Zebrafish Proteins; C459599:irx1b protein, zebrafish