Abstract:Transforming growth factor betas are integral molecular components of the signalling cascades defining development and survival of several neuronal groups. Among TGF-β ligands, TGF-β2 has been considered as relatively more important during development. We have generated a conditional knockout mouse of the Tgf-β2 gene with knock-in of an EGFP reporter and subsequently a mouse line with cell-type specific deletion of TGF-β2 ligand from Krox20 expressing cells (i.e., in cells from rhombomeres r3 and r5). We perfo… Show more
“…involved in the development of serotonergic neurons and in the synthesis of serotonin (Chleilat et al, 2019), SLC6A4: the serotonin transporter gene (Ramamoorthy et al, 1993), and SLC22A3: also a transporter of serotonin as well as of other neurotransmitters (dopamine and norepinephrine: Zhu et al, 2010). This is in line with TA B L E 1 (Continued)…”
Section: Upregulatedsupporting
confidence: 63%
“…Among the genes with the largest expression differences (Figure 2a,b, Table S5), we found genes with suspected functions in development. This included transforming growth factor β-2 (TGFB2); Figure 3a): a pleiotropic cytokine that recent findings link to the development of serotonergic neurons and the synthesis and metabolism of serotonin (Chleilat et al, 2019), and potassium channel tetramerization domain (KCTD21); Figure . 3b), which is expected to promote the degradation of HDAC1: an important protein regulating development via the Hedgehog pathway (De Smaele et al, 2011) and also involved in the regulation of the circadian clock (Takahashi, 2017). We also found genes linked to metabolism of sugars including SLC2A1 (facilitatative glucose transporter member 1, Figure 3c), which codes for the most important transporter of glucose and thereby of energy to the brain (Koch & Weber, 2019), and genes linked to the metabolism of lipids and steroids (e.g., CYP2G1, which may be related to the metabolism of steroid hormones: Hua et al, 1997, Figure 3d).…”
Section: Gene Expression Differences Associated To Dispersalmentioning
Although animal dispersal is known to play key roles in ecological and evolutionary processes such as colonization, population extinction and local adaptation, little is known about its genetic basis, particularly in vertebrates. Untapping the genetic basis of dispersal should deepen our understanding of how dispersal behaviour evolves, the molecular mechanisms that regulate it and link it to other phenotypic aspects in order to form the so‐called dispersal syndromes. Here, we comprehensively combined quantitative genetics, genome‐wide sequencing and transcriptome sequencing to investigate the genetic basis of natal dispersal in a known ecological and evolutionary model of vertebrate dispersal: the common lizard, Zootoca vivipara. Our study supports the heritability of dispersal in semi‐natural populations, with less variation attributable to maternal and natal environment effects. In addition, we found an association between natal dispersal and both variation in the carbonic anhydrase (CA10) gene, and in the expression of several genes (TGFB2, SLC6A4, NOS1) involved in central nervous system functioning. These findings suggest that neurotransmitters (serotonin and nitric oxide) are involved in the regulation of dispersal and shaping dispersal syndromes. Several genes from the circadian clock (CRY2, KCTD21) were also differentially expressed between disperser and resident lizards, supporting that the circadian rhythm, known to be involved in long‐distance migration in other taxa, might affect dispersal as well. Since neuronal and circadian pathways are relatively well conserved across vertebrates, our results are likely to be generalisable, and we therefore encourage future studies to further investigate the role of these pathways in shaping dispersal in vertebrates.
“…involved in the development of serotonergic neurons and in the synthesis of serotonin (Chleilat et al, 2019), SLC6A4: the serotonin transporter gene (Ramamoorthy et al, 1993), and SLC22A3: also a transporter of serotonin as well as of other neurotransmitters (dopamine and norepinephrine: Zhu et al, 2010). This is in line with TA B L E 1 (Continued)…”
Section: Upregulatedsupporting
confidence: 63%
“…Among the genes with the largest expression differences (Figure 2a,b, Table S5), we found genes with suspected functions in development. This included transforming growth factor β-2 (TGFB2); Figure 3a): a pleiotropic cytokine that recent findings link to the development of serotonergic neurons and the synthesis and metabolism of serotonin (Chleilat et al, 2019), and potassium channel tetramerization domain (KCTD21); Figure . 3b), which is expected to promote the degradation of HDAC1: an important protein regulating development via the Hedgehog pathway (De Smaele et al, 2011) and also involved in the regulation of the circadian clock (Takahashi, 2017). We also found genes linked to metabolism of sugars including SLC2A1 (facilitatative glucose transporter member 1, Figure 3c), which codes for the most important transporter of glucose and thereby of energy to the brain (Koch & Weber, 2019), and genes linked to the metabolism of lipids and steroids (e.g., CYP2G1, which may be related to the metabolism of steroid hormones: Hua et al, 1997, Figure 3d).…”
Section: Gene Expression Differences Associated To Dispersalmentioning
Although animal dispersal is known to play key roles in ecological and evolutionary processes such as colonization, population extinction and local adaptation, little is known about its genetic basis, particularly in vertebrates. Untapping the genetic basis of dispersal should deepen our understanding of how dispersal behaviour evolves, the molecular mechanisms that regulate it and link it to other phenotypic aspects in order to form the so‐called dispersal syndromes. Here, we comprehensively combined quantitative genetics, genome‐wide sequencing and transcriptome sequencing to investigate the genetic basis of natal dispersal in a known ecological and evolutionary model of vertebrate dispersal: the common lizard, Zootoca vivipara. Our study supports the heritability of dispersal in semi‐natural populations, with less variation attributable to maternal and natal environment effects. In addition, we found an association between natal dispersal and both variation in the carbonic anhydrase (CA10) gene, and in the expression of several genes (TGFB2, SLC6A4, NOS1) involved in central nervous system functioning. These findings suggest that neurotransmitters (serotonin and nitric oxide) are involved in the regulation of dispersal and shaping dispersal syndromes. Several genes from the circadian clock (CRY2, KCTD21) were also differentially expressed between disperser and resident lizards, supporting that the circadian rhythm, known to be involved in long‐distance migration in other taxa, might affect dispersal as well. Since neuronal and circadian pathways are relatively well conserved across vertebrates, our results are likely to be generalisable, and we therefore encourage future studies to further investigate the role of these pathways in shaping dispersal in vertebrates.
“…Chleilat et al (2019) reports that TGFB2 is active in the embryonic mouse hindbrain floor, which suggests its importance in the formation of hindbrain serotonergic neurons. The same study also suggests that products from other genes, such as TGFB1 and TGFB3 , are unable to compensate for deficient TGFB2 product.…”
Loeys–Dietz syndrome (LDS) is a connective tissue disorder that commonly results in a dilated aorta, aneurysms, joint laxity, craniosynostosis, and soft skin that bruises easily. Neurodevelopmental abnormalities are uncommon in LDS. Two previous reports present a total of four patients with LDS due to pure 1q41 deletions involving TGFB2 (Gaspar et al., American Journal of Medical Genetics Part A, 2017, 173, 2289–2292; Lindsay et al., Nature Genetics, 2012, 44, 922–927). The current report describes an additional five patients with similar deletions. Seven of the nine patients present with some degree of hypotonia and gross motor delay, and three of the nine present with speech delay and/or intellectual disability (ID). The smallest deletion common to all patients is a 785 kb locus that contains two genes: RRP15 and TGFB2. Previous studies report that TGFB2 knockout mice exhibit severe perinatal anomalies (Sanford et al., Development, 1997, 124, 2659–2670) and TGFB2 is expressed in the embryonic mouse hindbrain floor (Chleilat et al., Frontiers in Cellular Neuroscience, 2019, 13). The deletion of TGFB2 may be associated with a neurodevelopmental phenotype with incomplete penetrance and variable expression.
“…In the present work we have focused our attention only on TGF-β1, starting from the evidence that a selective deficit of this cytokine/neurotrophic factor has been found in major depressed patients (Myint et al, 2005), whereas no studies both in humans and animal models of depression show a deficit of TGF-β2. We cannot exclude a role for TGF-β2 in depression, because this neurotrophic factor is expressed in the dentate gyrus and it is also known to modulate serotonin synthesis and metabolism (Chleilat et al, 2019).…”
Section: Molecular Mechanisms Underlying Vulnerability To Depression ...mentioning
Stressful experiences early in life, especially in the prenatal period, can increase the risk to develop depression during adolescence. However, there may be important qualitative and quantitative differences in outcome of prenatal stress (PNS), where some individuals exposed to PNS are vulnerable and develop a depressive-like phenotype, while others appear to be resilient. PNS exposure, a well-established rat model of early life stress, is known to increase vulnerability to depression and a recent study demonstrated a strong interaction between transforming growth factor-β1 (TGF-β1) gene and PNS in the pathogenesis of depression. Moreover, it is well-known that the exposure to early life stress experiences induces brain oxidative damage by increasing nitric oxide levels and decreasing antioxidant factors. In the present work, we examined the role of TGF-β1 pathway in an animal model of adolescent depression induced by PNS obtained by exposing pregnant females to a stressful condition during the last week of gestation. We performed behavioral tests to identify vulnerable or resilient subjects in the obtained litters (postnatal day, PND > 35) and we carried out molecular analyses on hippocampus, a brain area with a key role in the pathogenesis of depression. We found that female, but not male, PNS adolescent rats exhibited a depressive-like behavior in forced swim test (FST), whereas both male and female PNS rats showed a deficit of recognition memory as assessed by novel object recognition test (NOR). Interestingly, we found an increased expression of type 2 TGF-β1 receptor (TGFβ-R2) in the hippocampus of both male and female resilient PNS rats, with higher plasma TGF-β1 levels in male, but not in female, PNS rats. Furthermore, PNS induced the activation of oxidative stress pathways by increasing inducible nitric oxide synthase (iNOS), NADPH oxidase 1 (NOX1) and NOX2 levels in the hippocampus of both male and female PNS adolescent rats. Our data suggest that high levels of TGF-β1 and its receptor TGFβ-R2 can significantly increase the resiliency of adolescent rats to PNS, suggesting that TGF-β1 pathway might represent a novel pharmacological target to prevent adolescent depression in rats.
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