Developmental Requirement of Homeoprotein Otx2 for Specific Habenulo-Interpeduncular Subcircuits

Abstract

The habenulo-interpeduncular system (HIPS) is now recognized as a critical circuit modulating aversion, reward, and social behavior. There is evidence that dysfunction of this circuit leads to psychiatric disorders. Because psychiatric diseases may originate in developmental abnormalities, it is crucial to investigate the developmental mechanisms controlling the formation of the HIPS. Thus far, this issue has been the focus of limited studies. Here, we explored the developmental processes underlying the formation of the medial habenula (MHb) and its unique output, the interpeduncular nucleus (IPN), in mice independently of their gender. We report that the Otx2 homeobox gene is essential for the proper development of both structures. We show that MHb and IPN neurons require Otx2 at different developmental stages and, in both cases, Otx2 deletion leads to disruption of HIPS subcircuits. Finally, we show that Otx2 ϩ neurons tend to be preferentially interconnected. This study reveals that synaptically connected components of the HIPS, despite radically different developmental strategies, share high sensitivity to Otx2 expression.

Multiple Regionalized Genes and Their Putative Networks in the Interpeduncular Nucleus Suggest Complex Mechanisms of Neuron Development and Axon Guidance

“…: they were expressed in at least one of the principal domains of the IPN (Pro, IPR, IPC). This segmentation of the IPN was initially proposed in the chick ( Lorente-Cánovas et al, 2012 ) and later confirmed in the mouse ( Moreno-Bravo et al, 2014 ; Ruiz-Reig et al, 2019 ; García-Guillén et al, 2020 ). Here, we further characterized the molecular profiles for each anteroposterior segment of the IPN located in their respective neuromeric units (Ist, r1-r and r1-c: Aroca and Puelles, 2005 ; Alonso et al, 2013 ).…”

“…The Chrna5 expressing population of the IPR in the IPN receives direct ventral MHb input and projects to other specific brainstem structures ( Hsu et al, 2013 ). By contrast, habenular Otx2 neurons target IPC cells that also express Otx2 ( Ruiz-Reig et al, 2019 ). Thus, the expression of some the genes in the IPN could be responsible for the generation of sub-circuits between neurons of the MHb, the IPN and its efferents.…”

“…Both the IPR and IPC are further divided along the mediolateral and dorsoventral axes into several sub-nuclei ( Lorente-Cánovas et al, 2012 ). Subsequently, it was shown that this a nucleus follows a similar developmental course in mice ( Moreno-Bravo et al, 2014 ; Ruiz-Reig et al, 2019 ; García-Guillén et al, 2020 ).…”

Netrin-1/DCC Signaling Differentially Regulates the Migration of Pax7, Nkx6.1, Irx2, Otp, and Otx2 Cell Populations in the Developing Interpeduncular Nucleus

“…Neuronal migration is an important feature of brain development, in some cases involving the displacement of considerable cell populations toward different coordinates. In addition to the classic examples of migration, such as that in the precerebellar nuclei (Bloch-Gallego et al, 2005), recent data has shown that complex migratory events contribute to the formation of the interpeduncular nucleus (IPN) (Lorente-Cánovas et al, 2012;Moreno-Bravo et al, 2014;Ruiz-Reig et al, 2019). In vertebrates, the IPN is a complex hindbrain structure and it is the principal target of the retroflex tract that comes from the medial habenula (mHb) (Herkenham and Nauta, 1979;Contestabile and Flumerfelt, 1981).…”

“…In behavioral and functional studies, the mHb-IPN pathway has been implicated in learning and memory, affective states and mood-related psychiatric conditions (Klemm, 2004;Hikosaka, 2010). However, the development of the IPN has only recently been studied, in particular in the chick (Lorente-Cánovas et al, 2012) and mouse (Moreno-Bravo et al, 2014;Ruiz-Reig et al, 2019).…”