Biomedical subjects

Simone M Smits

Publications and source records attributed to Simone M Smits.

8 recordsLinked to original sources

PubMed2006

Developmental origin and fate of meso-diencephalic dopamine neurons.

Specific vulnerability of substantia nigra compacta neurons as compared to ventral tegmental area neurons, as emphasized in Parkinson's disease, has been studied for many years and is still not well understood. The molecular codes and mechanisms that drive development of these structures have recently been studied through the use of elegant genetic ablation experiments. The data suggested that specific genes at specific anatomical positions in the ventricular zone are crucial to drive development of young neurons into the direction of the dopaminergic phenotype. In addition, it has become clear the these dopaminergic neurons are present in the diencephalon and in the mesencephalon and that they may contain a specific molecular signature that defines specific subsets in terms of position and function. The data indicate that these specific subsets may explain the specific response of these neurons to toxins and genetic ablation.

Amino Acid Sequence↗

PubMed2005

Molecular and cellular alterations in the Pitx3-deficient midbrain dopaminergic system.

Parkinson's disease (PD) is a progressive neurodegenerative disorder characterized by loss of midbrain dopaminergic (mDA) neurons in the substantia nigra compacta (SNc). In order to provide insights into adaptive mechanisms of the mDA system in pathology, specific molecular and cellular parameters of the mDA system were studied in Pitx3-deficient Aphakia (ak) mice, which suffer from severe developmental failure of SNc mDA neurons. Here, we demonstrate differential changes in striatal gene expression, reflecting the specific neuronal loss in these mice. In addition, the neuronal activity of remaining mDA neurons in the ventral tegmental area (VTA) was significantly increased in ak mice. In conclusion, ak mice display specific molecular and cellular alterations in the mDA system that provide new insights in compensatory mechanisms present in mDA-associated disorders such as PD.

Adaptation, Physiological↗

PubMed2004

Homeobox gene Pitx3 and its role in the development of dopamine neurons of the substantia nigra.

The homeobox gene Pitx3 plays an important part in the development and function of vertebrate midbrain dopaminergic neurons. Re-localization of the genetic defect in the mouse mutant aphakia to the Pitx3 locus, together with the subsequent identification of two deletions causing the gene to be silent, has been the hallmark of several studies into the role of Pitx3. In this review, we summarize the data and reflect on the role of Pitx3 in the development of dopamine neurons in the midbrain. The data indicate that Pitx3 is essential for the survival of dopamine neurons located in the substantia nigra compacta during development. Molecular analysis of the underlying mechanisms might provide new insights for understanding the selective degeneration observed in Parkinson patients.

Animals↗

PubMed2004

Species differences in brain pre-pro-neurotensin/neuromedin N mRNA distribution: the expression pattern in mice resembles more closely that of primates than rats.

We have used in situ hybridization to determine the distribution of pre-pro-neurotensin/neuromedin N (NT/N) mRNA in the brain of mice and rats. In rats and mice, expression was observed in the lateral septal nucleus, nucleus accumbens, medial preoptic area, bed nucleus of the stria terminalis, lateral hypothalamus, central amygdaloid nucleus and the subicilum. However, several differences in the NT/N mRNA distribution were observed between rats and mice in other brain areas. In mice, NT/N expression was detected in the subthalamic nucleus and geniculate nucleus, whereas expression was not observed in these brain areas in rats. Surprisingly, expression was not observed in mouse mesencephalic dopaminergic (mesDA) neurons and the CA1 area of the hippocampus, areas known to contain NT/N mRNA in the rat brain. Taken together, these results show that although the brain NT/N mRNA distribution largely overlaps in mice and rats, species differences exist in specific brain areas in rodents. Moreover, these data indicate that the distribution in mice resembles most that of primates than rats.

Animals↗

PubMed2004

The neuregulin receptor, ErbB4, is not required for normal development and adult maintenance of the substantia nigra pars compacta.

Degeneration of dopaminergic neurons in the substantia nigra is associated with one of the most prominent human neurological disorders, Parkinson's disease. It is therefore of high interest to identify molecules with trophic effects on this neuronal population. We show here that the neuregulin receptor ErbB4 is differentially expressed in mesencephalic dopaminergic neurons, found in the substantia nigra and in a subregion of the ventral tegmentum but not in the retrorubral field. Early developmental onset and continued expression of ErbB4 into the adult and the presence of two high affinity ligands, neuregulin-1 and betacellulin, in the basal ganglia, suggested that these molecules might participate in the differentiation and/or maintenance of the nigrostriatal system. In order to address this hypothesis, we used a loxP flanked ErbB4 allele in combination with a nestin-Cre transgene and generated brain-specific ErbB4 null mice. These mutant animals survived into adulthood. The distribution of dopaminergic cell bodies in the midbrain, the expression of numerous genes specific to mesencephalic dopaminergic neurons, and the axonal projection to the basal ganglia all appeared normal. Finally, an assessment of their motor function revealed no behavioral deficits. The apparent lack of any mutant phenotype suggests the presence of a strong compensatory mechanism.

Aging↗

PubMed2004

Early developmental failure of substantia nigra dopamine neurons in mice lacking the homeodomain gene Pitx3.

The mesencephalic dopamine (mesDA) system is involved in the control of movement and behavior. The expression of Pitx3 in the brain is restricted to the mesDA system and the gene is induced relatively late, at E11.5, a time when tyrosine hydroxylase (Th) gene expression is initiated. We show here that, in the Pitx3-deficient aphakia (ak) mouse mutant, the mesDA system is malformed. Owing to the developmental failure of mesDA neurons in the lateral field of the midbrain, mesDA neurons are not found in the SNc and the projections to the caudate putamen are selectively lost. However, Pitx3 is expressed in all mesDA neurons in control animals. Therefore, mesDA neurons react specifically to the loss of Pitx3. Defects of motor control where not seen in the ak mice, suggesting that other neuronal systems compensate for the absence of the nigrostriatal pathway. However, an overall lower activity was observed. The results suggest that Pitx3 is specifically required for the formation of the SNc subfield at the onset of dopaminergic neuron differentiation.

Animals↗

PubMed2003

Molecular mechanisms underlying midbrain dopamine neuron development and function.

The mesencephalic dopaminergic system is involved in the control of multiple brain functions including movement control and emotion and is of clinical importance because it is implicated in several psychiatric disorders, of which many are considered to have a neurodevelopmental origin. Studies into the developmental pathways of these neurons have led to the identification of the transcription factors En1, Pitx3, Nurr1 and Lmx1b, all shown to be important for the development of the mesencephalic dopaminergic system. In this paper, we discuss the consequences of genetic ablation of essential developmental genes. Furthermore, we discuss the consequences of changes in dopamine homeostasis for the function of the mesencephalic dopaminergic system. Finally, we analyse the potential of the mesencephalic dopaminergic system to adapt to gene dysfunction.

Animals↗

PubMed2003

Involvement of Nurr1 in specifying the neurotransmitter identity of ventral midbrain dopaminergic neurons.

The mesencephalic dopaminergic (mesDA) system is involved in many brain functions including motor control and motivated behaviour, and is of clinical importance because of its implication in psychiatric disorders and Parkinson's disease. Nurr1, a member of the nuclear hormone receptor superfamily of transcription factors, is essential for establishing the dopaminergic phenotype, because expression of tyrosine hydroxylase (TH), the rate-limiting enzyme in dopamine synthesis, requires Nurr1. In addition, Nurr1 plays an important role in the maintenance of mesDA neurons. Neonatal Nurr1 knockout mice lack expression of the dopamine transporter (DAT), the vesicular monoamine transporter 2 (VMAT2) and l-aromatic amino acid decarboxylase (AADC) in addition to TH specifically in mesDA neurons. It is unclear whether the lack of expression of these dopaminergic markers is caused by a maintenance defect or whether the induction of these markers depends on Nurr1 expression. To address this problem, the expression of DAT, VMAT2 and AADC was analysed at embryonic day 12.5 and 14.5. Here we demonstrate that induction of VMAT2 and DAT specifically in mesDA neurons requires Nurr1 expression, whereas AADC expression in mesDA neurons is induced independently of Nurr1 function.

Animals↗