Abstract
The habenulae are highly conserved nuclei in the dorsal diencephalon that connect the forebrain to the midbrain and hindbrain. These nuclei have been implicated in a broad variety of behaviours in humans, primates, rodents and zebrafish. Despite this, the molecular mechanisms that control the genesis and differentiation of neural progenitors in the habenulae remain relatively unknown. We have previously shown that, in zebrafish, the timing of habenular neurogenesis is left-right asymmetric and that in the absence of Nodal signalling this asymmetry is lost. Here, we show that habenular neurogenesis requires the homeobox transcription factor Pax6a and the redundant action of two proneural bHLH factors, Neurog1 and Neurod4. We present evidence that Hedgehog signalling is required for the expression of pax6a, which is in turn necessary for the expression of neurog1 and neurod4. Finally, we demonstrate by pharmacological inhibition that Hedgehog signalling is required continuously during habenular neurogenesis and by cell transplantation experiments that pathway activation is required cell autonomously. Our data sheds light on the mechanism underlying habenular development that may provide insights into how Nodal signalling imposes asymmetry on the timing of habenular neurogenesis.
Highlights
The Dorsal Diencephalic Conduction system (DDC) is a highly conserved neural circuit in the brain that consists of a pair of epithalamic nuclei, the habenulae, and two associated fibre tracts, the stria medullaris that carries axonal afferences from various area of the forebrain to the habenulae and the fasciculus retroflexus that conducts efferent axons from the habenulae to various midbrain/hindbrain target nuclei including the intrapeduncular nucleus or IPN [1,2]
Habenular neurogenesis requires the redundant activity of neurog1 and neurod4
We conclude that the redundant proneural activity of neurog1 and neurod4 is required for habenular neurogenesis
Summary
The Dorsal Diencephalic Conduction system (DDC) is a highly conserved neural circuit in the brain that consists of a pair of epithalamic nuclei, the habenulae, and two associated fibre tracts, the stria medullaris that carries axonal afferences from various area of the forebrain to the habenulae and the fasciculus retroflexus that conducts efferent axons from the habenulae to various midbrain/hindbrain target nuclei including the intrapeduncular nucleus or IPN [1,2]. Pax and Proneural Factors in Habenular Neurogenesis http://www.frc.asso.fr); The Association pour la Recherche sur le Cancer (ARC; http://www.fondationarc.org) [SFI20101201699 and PJA 20131200173 to P.B.]; The Federation of European Biochemical Societies (FEBS; //www.febs.org). R.M. was financed by the Ministère de la Recherche and ARC, C.H. by the CNRS, P.B. by INSERM and M.R. by FEBS, FRM and CNRS. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript
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