8 research outputs found
Abnormal development of monoaminergic neurons is implicated in mood fluctuations and bipolar disorder
Subtle mood fluctuations are normal emotional experiences, whereas drastic mood swings can be a manifestation of bipolar disorder (BPD). Despite their importance for normal and pathological behavior, the mechanisms underlying endogenous mood instability are largely unknown. During embryogenesis, the transcription factor Otx2 orchestrates the genetic networks directing the specification of dopaminergic (DA) and serotonergic (5-HT) neurons. Here we behaviorally phenotyped mouse mutants overexpressing Otx2 in the hindbrain, resulting in an increased number of DA neurons and a decreased number of 5-HT neurons in both developing and mature animals. Over the course of 1 month, control animals exhibited stable locomotor activity in their home cages, whereas mutants showed extended periods of elevated or decreased activity relative to their individual average. Additional behavioral paradigms, testing for manic-and depressive-like behavior, demonstrated that mutants showed an increase in intra-individual fluctuations in locomotor activity, habituation, risk-taking behavioral parameters, social interaction, and hedonic-like behavior. Olanzapine, lithium, and carbamazepine ameliorated the behavioral alterations of the mutants, as did the mixed serotonin receptor agonist quipazine and the specific 5-HT 2C receptor agonist CP-809101. Testing the relevance of the genetic networks specifying monoaminergic neurons for BPD in humans, we applied an interval-based enrichment analysis tool for genome-wide association studies. We observed that the genes specifying DA and 5-HT neurons exhibit a significant level of aggregated association with BPD but not with schizophrenia or major depressive disorder. The results of our translational study suggest that aberrant development of monoaminergic neurons leads to mood fluctuations and may be associated with BPD
Dusp16 Deficiency Causes Congenital Obstructive Hydrocephalus and Brain Overgrowth by Expansion of the Neural Progenitor Pool
Hydrocephalus can occur in children alone or in combination with other neurodevelopmental disorders that are often associated with brain overgrowth. Despite the severity of these disorders, the molecular and cellular mechanisms underlying these pathologies and their comorbidity are poorly understood. Here, we studied the consequences of genetically inactivating in mice dual-specificity phosphatase 16 (Dusp16), which is known to negatively regulate mitogen-activated protein kinases (MAPKs) and which has never previously been implicated in brain development and disorders. Mouse mutants lacking a functional Dusp16 gene (Dusp16 =) developed fully-penetrant congenital obstructive hydrocephalus together with brain overgrowth. The midbrain aqueduct in Dusp16 = mutants was obstructed during mid-gestation by an expansion of neural progenitors, and during later gestational stages by neurons resulting in a blockage of cerebrospinal fluid (CSF) outflow. In contrast, the roof plate and ependymal cells developed normally. We identified a delayed cell cycle exit of neural progenitors in Dusp16 = mutants as a cause of progenitor overproliferation during midgestation. At later gestational stages, this expanded neural progenitor pool generated an increased number of neurons associated with enlarged brain volume. Taken together, we found that Dusp16 plays a critical role in neurogenesis by balancing neural progenitor cell proliferation and neural differentiation. Moreover our results suggest that a lack of functional Dusp16 could play a central role in the molecular mechanisms linking brain overgrowth and hydrocephalus.Peer reviewe
In <i>Lmx1b</i><sup><i>-/-</i></sup> embryos NURR1<sup>+</sup> neurons express LMX1A and FOXA2 but not EN1.
<p>Representative coronal midbrain section of E12.5 WT (A, E, I, M), <i>En1</i><sup>+/Otx2</sup>(B, F, J, N), <i>Lmx1b</i><sup><i>-/-</i></sup> (C, G, K, O) and <i>En1</i><sup>+/Otx2</sup>; <i>Lmx1b</i><sup><i>-/-</i></sup>(D, H, L, P) embryos. LMX1A (A-H) and FOXA2 (I-L), which are important for the formation of the mdDA precursor domain do not show any changes in expression in <i>Lmx1b</i><sup><i>-/-</i></sup> or in <i>En1</i><sup>+/Otx2</sup>;<i>Lmx1b</i><sup><i>-/-</i></sup> embryos. In contrast EN1 (O) is lost in NURR1<sup>+</sup> neurons in <i>Lmx1b</i><sup><i>-/-</i></sup> mutants. In <i>En1</i><sup>+/Otx2</sup>;<i>Lmx1b</i><sup><i>-/-</i></sup> embryos (P), <i>Otx2</i> is not sufficient to rescue the EN1 expression lost in <i>Lmx1b</i><sup><i>-/-</i></sup>. (Scale bar, A-D, I-P, 100 ÎĽm, E-H 6 ÎĽm).</p
Overexpressing <i>Otx2</i> in the hindbrain leads ventrally to a specific expansion of the mdDA neuronal population.
<p>Representative coronal (A-P) and parasagittal (Q-T) sections of midbrain and hindbrain regions of WT (A-H, Q-R) and <i>En1</i><sup>+/Otx2</sup> embryos (I-P, S-T). (A-C, I-K) In the ventral midbrain of WT and of <i>En1</i><sup>+/Otx2</sup> mutants, NKX6.1 and the RN as visualized by POU4F1 are laterally adjacent to the mdDA neurons. (F-H) In the ventral hindbrain of WT mdDA markers are not observed and the NKX6.1 shows an expression pattern typical for the rostal hindbrain. (N-P) In the ventral hindbrain of <i>En1</i><sup>+/Otx2</sup>mutants the mdDA markers NURR1 and TH are present, but laterally not flanked by the RN or by the ventricular NKX6.1 expression domain (arrow). (D-E, L-M) In the dorsal midbrain of <i>En1</i><sup>+/Otx2</sup>embryos, POU4F1 and the proliferation marker PHH3 are increased. (Q, R) In WT, <i>Otx2</i> and <i>Lmx1b</i> expression extend until the isthmic constriction (indicated by arrow) marking the caudal border of the midbrain. In <i>En1</i><sup>+/Otx2</sup> mutants the caudally extended <i>Otx2</i> expression domain leads to a concomitant caudal extension of the <i>Lmx1b</i> expression domain. (Scale bar, 100 ÎĽm).</p
<i>Otx2</i> requires <i>Lmx1b</i> for the development of mdDA neurons.
<p>Representative coronal midbrain section of E12.5 WT (A-B, K-L), <i>En1</i><sup>+/Otx2</sup>(C-D, M-N), <i>Lmx1b</i><sup><i>-/-</i></sup> (E-F, O-P) and <i>En1</i><sup>+/Otx2</sup>; <i>Lmx1b</i><sup><i>-/-</i></sup> (G-H, Q-R) embryos. (I-J) Quantification of TH<sup>+</sup> neurons and ratio of TH<sup>+</sup>-NURR1<sup>+</sup>neurons in different gentypes. (C-D) In <i>En1</i><sup>+/Otx2</sup> embryos the number of TH<sup>+</sup> and NURR1<sup>+</sup> neurons is increased. (E, F) In <i>Lmx1b</i><sup><i>-/-</i></sup> embryos, <i>Otx2</i> is downregulated and TH<sup>+</sup> neurons are reduced in the medial region of the mdDA precursor domain and missing in the lateral domain (dotted line indicate border between medial and lateral region). (G, H) In <i>En1</i><sup>+/Otx2</sup>;<i>Lmx1b</i><sup><i>-/-</i></sup> mutants <i>Otx2</i> is not sufficient to induce the terminal differentiation of NURR<sup>+</sup>TH<sup>-</sup> cells to fully differentiated NURR<sup>+</sup>TH<sup>+</sup> mdDA neurons and to rescue the lateral TH<sup>+</sup> mdDA neurons. (I) Compared to the number of TH<sup>+</sup> neurons in WT, the number of TH neurons in <i>En1</i><sup>+/Otx2</sup> mutants are significantly increased and decreased in <i>Lmx1b</i><sup><i>-/-</i></sup> and <i>En1</i><sup>+/Otx2</sup>; <i>Lmx1b</i><sup><i>-/-</i></sup> embryos. (K, L) In WT there is a clear border between the mdDA neurons and the POU4F1 and LIM1/2 expression domain. (M, N) In <i>En1</i><sup>+/Otx2</sup> mutants the border is maintained, but the mdDA neuronal population is expanded laterally, without affecting the size of the RN. (O, P) In <i>Lmx1b</i><sup><i>-/-</i></sup>, POU4F1<sup>+</sup> and LIM1/2<sup>+</sup> cells are mixed with NURR1<sup>+</sup> neurons. (Q, R) In <i>En1</i><sup>+/Otx2</sup>;<i>Lmx1b</i><sup><i>-/-</i></sup> mutants <i>Otx2</i> did not re-establish the lateral border of the mdDA precursor field. (Scale bar, 100 ÎĽm).</p
<i>Lmx1b</i><sup><i>-/-</i></sup> embryos show a specific spatio-temporal loss of <i>En1</i> and <i>Wnt1</i> expression.
<p>Representative sagittal sections of the mesencephalic flexure of WT (A-R) and <i>Lmx1b</i><sup><i>-/-</i></sup> (A'-R') embryos at E11.5 (A-I, A'-I') and E12.5 (J-R, J'-R'). Genes were visualized by radioactive mRNA <i>in situ</i> hybridization. (A-F, A'-F') At E11.5, <i>En1</i> and <i>Wnt1</i> expressions are lost in <i>Lmx1b</i><sup><i>-/-</i></sup> embryos at the rostrolateral aspect of the mesencephalic flexure (arrow) and only the caudomedial expression domain is detectable (arrow head). (G-I, G'-I') The expression of <i>Lmx1a</i> is similar between the WT and the <i>Lmx1b</i><sup><i>-/-</i></sup>, including the rostrolateral domain (arrow). (J-L, J'-L') At E12.5, the caudomedial <i>En1</i> expression domain is lost in <i>Lmx1b</i><sup><i>-/-</i></sup>, while the hindbrain <i>En1</i> expression is still present. (P-R, P'-R') <i>Th</i> expression is significantly reduced. (M-O, M'-O'). No significant difference was found in the expression of <i>Nurr1</i>. Red dotted line represent boundary between midbrain and hindbrain. (Scale bar, 250 ÎĽm).</p