Abstract
BackgroundThe 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.ResultsWe 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.ConclusionsOur 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.
Highlights
The habenula and the thalamus are two critical nodes in the forebrain circuitry and they connect the midbrain and the cerebral cortex in vertebrates
Characterization of progenitors and precursors of habenular neurons To investigate the developmental program that controls the subdivision of p2 into the epithalamus and the thalamus, we began by looking for molecular markers that define the epithalamus, the habenula, in mouse embryos
Sonic hedgehog (Shh) function from the mid-diencephalic organizer (MDO) influences habenula formation In the set of experiments, we investigated if Pax6 and Shh regulate the formation of the epithalamus in zebrafish in a way similar to that found in the mouse embryo
Summary
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). The molecular regulation of the MDO Shh expression and the potential role of Shh in development of the habenula remain largely unclear. Based on gene expression patterns and morphological landmarks, the caudal forebrain is divided into three segments, prosomeres (p) and 3 [4,5]. We have recently shown that thalamic neuron precursor cells express homeobox gene Gbx, and the Gbx lineage defines a sharp compartment boundary between the habenula and thalamus in the mouse embryo [6], demonstrating a clear segregation of habenular and thalamic neurons. How the epithalamus diverges from the thalamus and pretectum is largely unknown
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Free) 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
