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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 Article has an altmetric score of 10

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

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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 4

Tangential and radial migration in coTshz1 mutants.

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Tangential and radial migration in coTshz1 mutants.
(A–D) After injectio...
(A–D) After injection with a pulse of BrdU and chasing for different lengths of time (A), BrdU+ cells (red, B–D) within the RMSOB (dotted white lines) were examined by immunohistology (blue, DAPI counterstain). Boxed regions in A denote areas analyzed in B–D. Per mil of BrdU+ cells in the RMSOB were also quantitated relative to total DAPI+ cells. (E) Coronal sections of 5-week-old OBs were analyzed after a 2-week chase and immunostained for BrdU (red), DCX (blue), and NeuN (green). Note the presence of many BrdU+ cells within the enlarged RMSOB of coTshz1 mutants containing DCX+ neuroblasts. The external plexiform layer (EPL), mitral cell layer (MCL), internal plexiform layer (IPL), granule cell layer, and RMSOB are indicated, as well as the anatomical midline of the RMSOB (dotted white line). (F) Percentage of BrdU+ cells located within 25 μm of the midline of the RMSOB in control and coTshz1 mice after a 2-week chase. Scale bars: 100 μm (B–E). **P < 0.01; ***P < 0.001.

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ISSN: 0021-9738 (print), 1558-8238 (online)

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