TSHZ1-dependent gene regulation is essential for olfactory bulb development and olfaction
Daniela Ragancokova, … , Hagen Wende, Alistair N. Garratt
Daniela Ragancokova, … , Hagen Wende, Alistair N. Garratt
Published February 3, 2014
Citation Information: J Clin Invest. ;124(3):1-14. https://doi.org/10.1172/JCI72466.
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Research Article Development Genetics Neuroscience

TSHZ1-dependent gene regulation is essential for olfactory bulb development and olfaction

Abstract

The olfactory bulb (OB) receives odor information from the olfactory epithelium and relays this to the olfactory cortex. Using a mouse model, we found that development and maturation of OB interneurons depends on the zinc finger homeodomain factor teashirt zinc finger family member 1 (TSHZ1). In mice lacking TSHZ1, neuroblasts exhibited a normal tangential migration to the OB; however, upon arrival to the OB, the neuroblasts were distributed aberrantly within the radial dimension, and many immature neuroblasts failed to exit the rostral migratory stream. Conditional deletion of Tshz1 in mice resulted in OB hypoplasia and severe olfactory deficits. We therefore investigated olfaction in human subjects from families with congenital aural atresia that were heterozygous for TSHZ1 loss-of-function mutations. These individuals displayed hyposmia, which is characterized by impaired odor discrimination and reduced olfactory sensitivity. Microarray analysis, in situ hybridization, and ChIP revealed that TSHZ1 bound to and regulated expression of the gene encoding prokineticin receptor 2 (PROKR2), a G protein–coupled receptor essential for OB development. Mutations in PROKR2 lead to Kallmann syndrome, characterized by anosmia and hypogonadotrophic hypogonadism. Our data indicate that TSHZ1 is a key regulator of mammalian OB development and function and controls the expression of molecules involved in human Kallmann syndrome.

Authors

Daniela Ragancokova, Elena Rocca, Anne M.M. Oonk, Herbert Schulz, Elvira Rohde, Jan Bednarsch, Ilse Feenstra, Ronald J.E. Pennings, Hagen Wende, Alistair N. Garratt

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Figure 6

Tshz1 mutations in mice result in severe olfactory deficits.

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Tshz1 mutations in mice result in severe olfactory deficits. (A) Buried...
(A) Buried food test. The latency of coTshz1 mutant mice to find hidden food pellets substantially increased, although these mice were capable of food detection after soaking pellets in vanillin. Dashed line denotes the maximal 15-minute test period (900s). (B) Preference test. Time spent sniffing at filter papers containing 1 of 3 odors (water, 2-methyl butyric acid [2-MB], and peanut butter, presented in random order) was determined. Whereas control mice tended to avoid 2-MB and were strongly attracted to peanut butter, no clear responses to aversive or attractive odors were seen in coTshz1 mutants. Gray and black dashed lines denote the investigation time of neutral odor (H2O) of control and coTshz1 mutant mice, respectively. (C) Habituation/dishabituation test. Animals were presented 3 times with different odors on cotton swabs in the order shown, and total time spent sniffing was determined. Inset shows fold change in investigation time in response to the presentation of a new smell (i.e., third test of previous odor compared with first test of next odor). *P < 0.05; **P < 0.01; ***P < 0.001.