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.

SP8 and SP9 coordinately promote D2-type medium spiny neuron production by activating Six3 expression

“…In the Sp8/9-DCKO mice, newly born neuroblasts in the dLGE and postnatal SVZ-RMS-OB fail to express Prokr2 and Tshz1 lack virtually all OB mature interneurons. We suggest that the lack of Prokr2 and Tshz1 RNA in large part accounts for the defects in differentiation and migration (tangential and radial) of OB immature interneurons, as similar phenotypes are observed in Prokr2 (and Tshz1) mutant mice (Ng et al, 2005;Matsumoto et al, 2006;Ragancokova et al, 2014;Li et al, 2017). Thus, in the dLGE and postnatal SVZ-RMS, Sp8 and Sp9 coordinately regulate OB interneuron development mainly by promoting Prokr2 and Tshz1 expression; however, here Sp8 has the leading role.…”

“…Third, Prokr2 and Tshz1 expression levels are reduced in the dLGE and postnatal SVZ of Sp8-CKO mice, but not in Sp9-KO mice (Li et al, 2017). Prokr2 and Tshz1 are known to promote OB neuronal differentiation and migration and are involved in human Kallmann syndrome (Ng et al, 2005;Matsumoto et al, 2006;Ragancokova et al, 2014).…”

Wnt signalling drives context-dependent differentiation or proliferation in neuroblastoma

“…Of the 90 DEGs identified by our RNA-seq, 53 have previously been implicated as Wnt target genes by β -catenin and TCF4 binding to their promoters. We identified numerous transcription factors downstream of Wnt signalling, many of which have been shown to be involved in neuronal differentiation and to act upstream of Wnt signalling (ASCL1 [42,54], MSX1 and MSX2 [41], LHX9 [55], and TSHZ1 [56]). This, together with the other transcription factors (EPAS1, ETS1, ETV6, TBX18, TSHZ2, ZEB2, ZBTB38), as well as epigenetic regulators/non-coding RNAs (HDAC9, KDM7A, LINC00327, TMEM108-AS1, VLDLR-AS1) strongly supports Wnt signalling as a master regulator of neuroblast cell fate.…”

GnRH, anosmia and hypogonadotropic hypogonadism – Where are we?

“…As suggested by mouse models in which prokineticin 2 ligand and receptor (PROK2/PROKR2) [155; 156; 157; 158; 159; 160], SEMA3A [149] or SOX10 genes have been knocked out or mutated [150], other forms of KS may be due to failure of the olfactory/terminal nerve fibers to establish proper contact with the forebrain [117; 147; 158; 161]. Lack of these fibers connecting with the brain can result from cell autonomous defects in olfactory neurons or defective formation of olfactory bulb (OB).…”