Spatiotemporal Role of Transforming Growth Factor Beta 2 in Developing and Mature Mouse Hindbrain Serotonergic Neurons

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 performed a phenotypic analysis of the hindbrain serotonergic system during development and in adulthood, determined the neurochemical profile in hindbrain and forebrain, and assessed behavioural performance of wild type and mutant mice. Mutant mice revealed significantly decreased number of caudal 5-HT neurons at embryonic day (E) 14, and impaired development of caudal dorsal raphe, median raphe, raphe magnus, and raphe obscurus neurons at E18, a phenotype that was largely restored and even overshot in dorsal raphe of mutant adult mice. Serotonin levels were decreased in hindbrain but significantly increased in cortex of adult mutant mice, though without any behavioural consequences. These results highlight differential and temporal dependency of developing and adult neurons on TGF-β2. The results also indicate TGF-β2 being directly or indirectly potent to modulate neurotransmitter synthesis and metabolism. The novel floxed TGF-β2 mouse model is a suitable tool for analysing the in vivo functions of TGF-β2 during development and in adulthood in many organs.

Investigating the genetic basis of vertebrate dispersal combining RNA‐seq, RAD‐seq and quantitative genetics

“…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)…”

“…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).…”

Loeys–Dietz syndrome caused by 1q41 deletion including TGFB2 is associated with a neurodevelopmental phenotype

“…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.…”

Prenatal stress induces a depressive-like phenotype in adolescent rats: The key role of TGF-β1 pathway

“…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).…”