TSHZ1-dependent gene regulation is essential for olfactory bulb development and olfaction.
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.
Daniela
D
Ragancokova
Elena
E
Rocca
Anne M M
AM
Oonk
Herbert
H
Schulz
Elvira
E
Rohde
Jan
J
Bednarsch
Ilse
I
Feenstra
Ronald J E
RJ
Pennings
Hagen
H
Wende
Alistair N
AN
Garratt
D000293:Adolescent; D000328:Adult; D000818:Animals; D016022:Case-Control Studies; D002454:Cell Differentiation; D002465:Cell Movement; D002648:Child; D000013:Congenital Abnormalities / Q000235:genetics; D004423:Ear / Q000002:abnormalities; D005136:Eye Proteins / Q000378:metabolism; D005260:Female; D015870:Gene Expression; D018507:Gene Expression Regulation, Developmental; D056726:Genetic Association Studies; D018398:Homeodomain Proteins / Q000235:genetics* / Q000378:metabolism / Q000502:physiology; D006801:Humans; D017436:Kallmann Syndrome / Q000235:genetics*; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D009474:Neurons / Q000502:physiology; D009830:Olfactory Bulb / Q000254:growth & development / Q000378:metabolism* / Q000473:pathology; D000071841:PAX6 Transcription Factor; D051761:Paired Box Transcription Factors / Q000378:metabolism; D043562:Receptors, G-Protein-Coupled / Q000235:genetics* / Q000378:metabolism; D018000:Receptors, Peptide / Q000235:genetics* / Q000378:metabolism; D012097:Repressor Proteins / Q000378:metabolism; D012903:Smell; D059467:Transcriptome
D005136:Eye Proteins; D018398:Homeodomain Proteins; D000071841:PAX6 Transcription Factor; C000605730:PAX6 protein, human; C470838:PROKR2 protein, human; D051761:Paired Box Transcription Factors; C000605732:Pax6 protein, mouse; D043562:Receptors, G-Protein-Coupled; D018000:Receptors, Peptide; D012097:Repressor Proteins; C569098:TSHZ1 protein, human