Analysis of genes within the schizophrenia-linked 22q11.2 deletion identifies interaction of <i>night owl/LZTR1</i> and <i>NF1</i> in GABAergic sleep control

Maurer, Gianna W.; Malita, Alina; Nagy, Stanislav; Kaburagi, Takashi; Werge, Thomas; Halberg, Kenneth A.; Texada, Michael J.; Rewitz, Kim

doi:10.1101/755454

“…To generate anti-Urn8R, anti-DH37 and anti-DH47 specific antibodies, we analyzed the amino acid sequence of the proteins to identify the most optimal immunizing peptide region according to a previously described method (59). These antibodies were subsequently used for immunocytochemistry (60) to visualize immunofluoresence in different tissues.…”

Section: Generation Of Antibodies and Visualization Of Ligands And Receptor Distributionmentioning

confidence: 99%

A unique Malpighian tubule architecture in Tribolium castaneum informs the evolutionary origins of systemic osmoregulation in beetles

Kaburagi

¹

,

Naseem

²

,

Kolosov

³

et al. 2021

Proc. Natl. Acad. Sci. U.S.A.

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Maintaining internal salt and water balance in response to fluctuating external conditions is essential for animal survival. This is particularly true for insects as their high surface-to-volume ratio makes them highly susceptible to osmotic stress. However, the cellular and hormonal mechanisms that mediate the systemic control of osmotic homeostasis in beetles (Coleoptera), the largest group of insects, remain largely unidentified. Here, we demonstrate that eight neurons in the brain of the red flour beetle Tribolium castaneum respond to internal changes in osmolality by releasing diuretic hormone (DH) 37 and DH47—homologs of vertebrate corticotropin-releasing factor (CRF) hormones—to control systemic water balance. Knockdown of the gene encoding the two hormones (Urinate, Urn8) reduces Malpighian tubule secretion and restricts organismal fluid loss, whereas injection of DH37 or DH47 reverses these phenotypes. We further identify a CRF-like receptor, Urinate receptor (Urn8R), which is exclusively expressed in a functionally unique secondary cell in the beetle tubules, as underlying this response. Activation of Urn8R increases K+ secretion, creating a lumen-positive transepithelial potential that drives fluid secretion. Together, these data show that beetle Malpighian tubules operate by a fundamentally different mechanism than those of other insects. Finally, we adopt a fluorescent labeling strategy to identify the evolutionary origin of this unusual tubule architecture, revealing that it evolved in the last common ancestor of the higher beetle families. Our work thus uncovers an important homeostatic program that is key to maintaining osmotic control in beetles, which evolved parallel to the radiation of the “advanced” beetle lineages.

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“…Locomotor assays. To analyze long-term locomotor activity of individual flies, we used the Drosophila activity monitor system (TriKinetics) in combination with the pySolo software package 74 and a custom MATLAB script (MATLAB R2016b, The MathWorks Inc, Natick, Massachusetts) as previously described 75 . Individual 4-day old flies of the appropriate genotype were housed in 65-mm-long glass tubes containing food (5% sucrose and 2% agar in water) in one end and a cotton plug in the other, which were assembled into the monitoring system.…”

Section: Methodsmentioning

confidence: 99%

A nutrient-responsive hormonal circuit mediates an inter-tissue program regulating metabolic homeostasis in adult Drosophila

Kaburagi

¹

,

Terhzaz

²

,

Naseem

³

et al. 2021

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Animals maintain metabolic homeostasis by modulating the activity of specialized organs that adjust internal metabolism to external conditions. However, the hormonal signals coordinating these functions are incompletely characterized. Here we show that six neurosecretory cells in the Drosophila central nervous system respond to circulating nutrient levels by releasing Capa hormones, homologs of mammalian neuromedin U, which activate the Capa receptor (CapaR) in peripheral tissues to control energy homeostasis. Loss of Capa/CapaR signaling causes intestinal hypomotility and impaired nutrient absorption, which gradually deplete internal nutrient stores and reduce organismal lifespan. Conversely, increased Capa/CapaR activity increases fluid and waste excretion. Furthermore, Capa/CapaR inhibits the release of glucagon-like adipokinetic hormone from the corpora cardiaca, which restricts energy mobilization from adipose tissue to avoid harmful hyperglycemia. Our results suggest that the Capa/CapaR circuit occupies a central node in a homeostatic program that facilitates the digestion and absorption of nutrients and regulates systemic energy balance.

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“…To generate antibodies specific against proteins of interest, we analyzed the amino acid (aa) sequence of the proteins to identify the most optimal immunizing peptide region according to a previously described method (60). For Urn8R, this analysis resulted in the selection of a peptide corresponding to aa 3-17 (WSEPLPQEPEPVDAD) in the N-terminal region of the full-length parent protein, which was then submitted for a custom immunization protocol carried out by Genosphere Biotechnologies (Paris, France).…”

Section: Methodsmentioning

confidence: 99%

A Unique Renal Architecture inTribolium castaneumInforms the Evolutionary Origins of Systemic Osmoregulation in Beetles

Kaburagi

¹

,

Mt

²

,

Kolosov

³

et al. 2020

Preprint

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Maintaining internal salt and water balance in response to fluctuating external conditions is essential for animal survival. This is particularly true for insects as their high surface-to-volume ratio makes them highly susceptible to osmotic stress. However, the cellular and hormonal mechanisms that mediate the systemic control of osmotic homeostasis in beetles (Coleoptera), the largest group of insects, remain largely unidentified. Here, we demonstrate that eight neurons in the brain of the red flour beetle Tribolium castaneum respond to internal changes in osmolality by releasing diuretic hormone (DH) 37 and DH47 – homologues of vertebrate corticotropinreleasing factor (CRF) hormones – to control systemic water balance. Knockdown of the gene encoding the two hormones (Urinate, Urn8) reduces renal secretion and restricts organismal fluid loss, whereas injection of DH37 or DH47 reverses these phenotypes. We further identify a novel CRF-like receptor, Urinate Receptor (Urn8R), which is exclusively expressed in a unique secondary cell (SC) in the beetle renal organs, as underlying this response. Activation of Urn8R increases K+ secretion specifically through SCs, creating a lumen-positive transepithelial potential that drives fluid secretion. Together, these data show that beetle renal organs operate by fundamentally different mechanism than those of other insects. Finally, we adopt a fluorescent labelling strategy to identify the evolutionary origin of this unusual renal architecture within the large Order of Coleoptera. Our work thus uncovers an important homeostatic program that is key to maintaining osmotic control in beetles, which evolved in parallel to the radiation of the higher beetle families.Significance StatementBeetles are the most diverse animal group on the planet. Their evolutionary success suggests unique physiological adaptations in overcoming water stress, yet the mechanisms underlying this ability are unknown. Here we use molecular genetic, electrophysiology and behavioral studies to show that a group of brain neurons responds to osmotic disturbances by releasing diuretic hormones that regulate salt and water balance. These hormones bind to their receptor exclusively localized to a unique secondary cell in the renal organs to modulate fluid secretion and organismal water loss. This renal architecture, common to all higher beetle families, is novel within the insects, and provides an important clue to the evolutionary success of the beetles in colonizing an astounding range of habitats on Earth.

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Analysis of genes within the schizophrenia-linked 22q11.2 deletion identifies interaction of night owl/LZTR1 and NF1 in GABAergic sleep control

Cited by 7 publications

References 74 publications

A unique Malpighian tubule architecture in Tribolium castaneum informs the evolutionary origins of systemic osmoregulation in beetles

A unique Malpighian tubule architecture in Tribolium castaneum informs the evolutionary origins of systemic osmoregulation in beetles

A nutrient-responsive hormonal circuit mediates an inter-tissue program regulating metabolic homeostasis in adult Drosophila

A Unique Renal Architecture inTribolium castaneumInforms the Evolutionary Origins of Systemic Osmoregulation in Beetles

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