Alwin Prem Anand A , Alvarez-Bolado G , Wizenmann A .

             regulation of gene expression
             neuron development

                autistic disorder
                Down syndrome
                schizophrenia

Figure 1. Gene expression, neurogenesis and gene regulation around the MHB. (A) Summary of gene expression patterns around the MHB. Otx2, Gbx2, Wnt1, Fgf8, En1/2, Pax2 -5 -8, and Notch are expressed in a similar pattern in all vertebrates. The expression pattern of Hes genes however differs between vertebrate species. For instance, the pattern of zebrafish her 9 is similar to that of chick HES5. (B) Pattern of neurogenesis around the chick MHB at HH17 (∼E3). Differentiated neurons were labeled with an antibody against medium weight neurofilament (RMO-270). The IZ lacks neurons at this stage, and in midbrain only the dorsally located MTN neurons have developed. ICN neurons are located in ventral diencephalon and form the medial longitudinal tract left and right of the FP. In r1 ventral and dorsal neurons have differentiated. (C) In all vertebrates studied, during the maintenance phase, Wnt1, Fgf8, Pax2/5/8, and En genes regulate each other to maintain the MHB. In zebrafish and chick, miR-9 suppresses Fgf8 expression and thus indirectly the expression of Wnt1, Pax, and En genes. The difference between both species is in the miR-9 targeting. In chick, Fgf8, and En1 are target genes of miR-9; where the former shows experimental reduction and the later is inconsistent (Alwin Prem Anand et al., 2018). In zebrafish, miR-9 promotes neurogenesis by inhibiting different Hes genes around and within the IZ (her9 and her5, respectively). In chick, none of the Hes genes expressed in and around the IZ are miR-9 targets (pink arrows). miR-9 OE in chick resulted in immature neurogenesis only in r1 and IZ but not in midbrain, These results suggests that at least in chick IZ and in hindbrain genes of the Hes pathway could be inhibited by miR-9. In chick midbrain, like in Xenopus telencephalon (Bonev et al., 2011) growth is reduced but without an effect on cell death as in Xenopus, which might be mediate by inhibiting the Wnt activator Zic1. The Models are modified from Rhinn and Brand (2001) and Delaloy and Gao (2008). Di, diencephalon; FP, floor plate; INC, interstitial nucleus of Cajal; IZ, intervening zone; MES, mesencephalon; MHB, mid-hindbrain boundary; MTN, mesencephalic trigeminal nucleus; Pros, prosencephalon; Rh, rhombencephalon; r1 to 4, rhombomeres 1–4.

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