AbstractsBiology & Animal Science

Vertebrate brain is one of the most complex and mysterious objects for biological research. Embryonic brain development involves stereotypic brain structure formation, and a vast number of precise intercellular connections are established for the generation of the highly complex circuitry of the brain. This work aims at explaining HMGB1 and AMIGO1 function in modulating vertebrate brain development. Hmgb1 knockdown zebrafish morphants produced by injection of morpholino oligonucleotides display severe defects in the forebrain and gross deteriorated catecholaminergic system. The morphant is also deficient in survival and proliferation of neural progenitors. Similar central nervous system (CNS) developmental defects have been observed in HMGB1 knockout mouse embryo. The HMGB1 null mouse embryonic brain cells showed much lower proliferating and differentiating activities compared to wild type animals. HMGB1 knockdown and knockout model respectively from zebrafish and mouse have confirmed that AMIGO1 expression is directly regulated by HMGB1. AMIGO1 regulates expression of Kv2.1 potassium channel during development, but the colocalization of AMIGO1 and Kv2.1 has only been observed in mouse and zebrafish adult brain. Furthermore, knockdown of amigo1 expression using morpholino oligonucleotides impairs the formation of fasciculated tracts in early fiber scaffolds of brain. The same defect can be also induced by mRNA-mediated expression of the Amigo1 ectodomain that inhibits adhesion mediated by the full-length protein. The impaired formation of neural circuitry is reflected in enhanced locomotor activity and attenuated escape responses. Our data demonstrate that HMGB1 is a critical factor for embryonic CNS development involved in many important developmental events. HMGB1 is essential for the neurogenesis and differentiation occurring at the developmental stage when forebrain structures are forming. Amigo1 is required for the development of neural circuits under the regulation of HMGB1. The mechanism involves homophilic interactions within the developing fiber tracts and regulation of the Kv2.1 potassium channel to form functional neural circuitry that controls locomotion. HMGB1 and AMIGO1 are both crucial for embryonic brain development and neural circuit formation. Selkärankaisen aivot ovat eräs monimutkaisimmista ja mysteerisimmistä biologisista tutkimuskohteista. Alkionkehityksen aikana aivoissa muodostuu lukemattomia määriä solujen välisiä yhteyksiä. Tämän väitöskirjatyön tavoitteena oli tutkia ja selvittää HMGB1 ja AMIGO1 molekyylien osuutta selkärankaisten aivojen kehityksessä. HMGB1 proteiinin ilmentymisen estäminen seeprakalan alkionkehityksen aikana saa aikaan vakavia kehityshäiriöitä etuaivoissa. HMGB1 proteiinin puute saa aikaa neuronaalisten kantasolujen vähentyneen jakautumisen sekä lisääntyneen kuoleman. Samanlaisia kehityshäiriöitä todettiin myös HMGB1 poistogeenisissä hiiren alkioissa. HMGB1 poistogeenisten hiirten alkioiden aivot osoittivat vähentynyttä solujen jakatumista sekä erilaistumista…