Transcription factor CUX2 and post-transcriptional factor CELF4 in neurons of synapse-enriched layers during human fetal corticogenesis

doctoral thesis

• Author: Terezija Miškić
• Mentor: Željka Krsnik (mentor)
• Committee member: Ivica Kostović (predsjednik povjerenstva)
• Committee member: Goran Šimić (član povjerenstva)
• Committee member: Mario Vukšić (član povjerenstva)
• Committee member: Dubravka Švob Štrac (član povjerenstva)
• Committee member: Nives Pećina-Šlaus (član povjerenstva)
• Granter: University of Zagreb; School of Medicine; Zagreb
• Defense date and country: 2022-01-05, Croatia
• Scientific / art field, discipline and subdiscipline: BIOMEDICINE AND HEALTHCARE; Basic Medical Sciences; Neuroscience
• Universal decimal classification (UDC): 61 - Medical sciences

Abstract

Cortical development of the human fetus is a protracted process filled with critical histogenetic events which give rise to the brain complexities differentiating in the transient neocortical compartments. Transcriptional and post-transcriptional mechanisms are the fundament of neurogenetic and histogenetic events, with the transcription and post-transcriptional factors acting as crucial impactors of neural development. In this thesis, spatio-temporal dynamics of CUX2 transcription factor and post-transcriptional factor, CELF4, in human fetal development are studied in depth. To explore their role in cortical development, human post-mortem fetal tissue from 8 PCW to 38 PCW, in addition to adult tissue was used for the experiments. The results show CUX2 nuclear expression in neurons of the transient compartments from 8 PCW to 38 PCW of the human fetal prospective frontal cortex, specifically in the CR cells of the MZ and in the neurons of the SP zone. Both CUX2 and CELF4 are expressed in the migratory cells, projection neuronal subpopulation, and in the subpopulation of interneurons. CELF4 positive neurons were found in the synaptophysin-immunoreactive synaptic strata during midgestation. We have also identified human early and midfetal mRNA binding targets of CELF4: TLE4, EIF4A2, VGLUT1, and SYNPR. In conclusion, CUX2 participates in the molecular specification, circuit formation, and synaptogenesis of fetal transient SP and MZ projection neurons as it does in permanent projection neurons of upper layers. CELF4 attains a role in cortical development, by regulating mRNAs involved in the processes of transcription regulation, axonal pathfinding, and synapse formation. The results of this thesis show the spatio-temporal expression pattern of TF, CUX2, and RBP, CELF4 in correlation with the dynamics of cortical processes taking place in the same laminae, which indicates their important roles in the differentiation of the cortex.

Abstract (english)

Razvoj moždane kore fetusa čovjeka je kompleksan proces, ispunjen ključnim histogenetskim zbivanjima koji se ostvaraju u prolaznim fetalnim zonama, a čiji učinci se vide u konačnoj složenosti funkcija ljudskoga mozga. Transkripcijski i post-transkripcijski mehanizmi su u pozadini neurogenetskih i histogenetskih događaja, te imaju izravan utjecaj na razvoj mozga. Tema ovog doktorskog istraživanja je analiza vremensko-prostornog obrasca ekspresije transkripcijskog faktora CUX2 i post-transkripcijskog faktora CELF4 tijekom fetalnog razvoja ljudskog mozga. Da bi istražili njihovu ulogu u razvoju moždane kore, korišteni su postmortalni uzorci mozga starosti od 8 PCW do 38 PCW, te dodatno uzorci odraslog mozga. Rezultati ovog istraživanja pokazuju da je CUX2 eksprimiran u jezgrama neurona prolaznih fetalnih zona u dobi od 8 do 38 PCW moždane kore čeonog režnja, a posebno unutar jezgara CR stanica marginalne zone (MZ) i neurona subplate (SP) zone. CUX2 i CELF4 su eksprimirani u migratornim stanicama, projekcijskim neuronima i u interneuronima moždane kore. CELF4 pozitivni neuroni su pronađeni unutar sinaptičkih slojeva koji su imunoreaktivni na sinaptofizin, tijekom midgestacije. Tijekom ranog i srednjeg fetalnog razdbolja CELF4 veže mRNA TLE4, EIF4A2, VGLUT1 i SYNPR. Zaključno, CUX2 sudjeluje u procesima molekularne specifikacije, organizacije neuralnih veza, i sinaptogeneze u fetalnim prolaznim MZ i SP projekcijskim neuronima, te u stalnim projekcijskim neuronima površnih slojeva moždane kore. Uloga CELF4 proteina u razvoju moždane kore je u regulaciji mRNA uključenih u procese regulacije transkripcije, navođenja aksona i formacije sinapsi. Rezultati ove disertacije prikazuju vremensko-prostorni ekspresijski obrazac transkripcijskog faktora CUX2 i RNA-vezujućeg proteina CELF4 u korelaciji sa dinamikom zbivanja u moždanoj kori koji se događaju u isto vrijeme u istim slojevima, te time odražavaju njihovu ulogu u diferencijaciji moždane kore.

• Keywords: Neurons; Synapses; Transcription Factors; RNA; Fetal Development; Frontal Lobe; Fetus; Interneurons
• Keywords (english): Neuroni Sinapse; Transkripcijski faktori; RNA; Razvoj fetusa; Frontalni režanj; Fetus; Interneuroni
• Language: english
• URN:NBN: urn:nbn:hr:105:843366
• Project: Number: KK.01.1.1.01.0007; Title: Eksperimentalna i klinička istraživanja hipoksijsko-ishemijskog oštećenja mozga u perinatalnoj i odrasloj dobi; Leader: Ivica Kostović; Jurisdiction: eu; Funder: EK
• Study programme: Title: Neuroscience; Study programme type: university; Study level: postgraduate; Academic / professional title: doktor/doktorica znanosti, područje biomedicine i zdravstva (doktor/doktorica znanosti, područje biomedicine i zdravstva)
• Type of resource: Text
• Extent: 103 str.
• File origin: Born digital
• Access conditions: Open access; Embargo expiration date: 2023-05-05
• Public note: Sumentor: Mladen-Roko Rašin
• Created on: 2022-03-31 08:43:05