Morfološke promjene projekcijskih neurona strijatuma u miša s humaniziranim oblikom gena Foxp2

doctoral thesis

• Title (english): Changes in morphology of projection striatal neurons in mice with humanized version of Foxp2 gene
• Author: Ivana Bičanić
• Mentor: Zdravko Petanjek (mentor)
• Committee member: nije dostupno (član povjerenstva)
• Granter: University of Zagreb; School of Medicine; Zagreb
• Defense date and country: 2017-04-26, Croatia
• Scientific / art field, discipline and subdiscipline: BIOMEDICINE AND HEALTHCARE; Basic Medical Sciences
• Universal decimal classification (UDC): 61 - Medical sciences

Abstract

Smatra se da FOXP2 gen ima važnu ulogu u neuralnim krugovima koji omogućavaju
procesiranje govora. Protein koji kodira taj gen se između čimpanze i čovjeka razlikuje u
samo dvije aminokiseline što govori u prilog njegove visoke konzerviranosti. U ljudi sa samo
jednim funkcionalnim alelom FOXP2 gena najizraženije strukturne promjene se nalaze u
strijatumu, što korelira s poremećajima govora. Transgenična varijanta čovječjeg gena dovela
je u miša do različitih elektrofizioloških promjena i promjena u ponašanju. Dosadašnja
istraživanja su implicirala i njegov utjecaj na rast dendritičkog stabla u neuronima u kojih je
izraženost Foxp2 najveća, a to su trnasti srednje veliki neuroni strijatuma. Cilj ovoga
istraživanja je bio detaljno analizirati morfologiju trnastih srednje velikih neurona strijatuma u
miševa divljeg tipa koristeći Golgi Cox metodu, utvrditi regionalne razlike u morfologiji
unutar strijatuma te vidjeti kako na njihovu morfologiju utječe humanizirani Foxp2 gen i
njegove dvije varijante (Foxp2T302N i Foxp2N324S). Naše istraživanje je pokazalo da između
transgeničnih životinja i njihovih kontrolnih skupina nije bilo značajnijih razlika u
neuronalnoj morfologiji, no uočene su regionalne razlike i to osobito u rostralnom i
kaudalnom dijelu strijatuma gdje neuroni u prosjeku imaju 15-20% veće dendritičko stablo,
ali uz različitu topologiju. Tako se u kaudalnim dijelovima proporcionalno povećava broj
segmenata, dok u rostralnim dijelovima to nije slučaj pa su u prosjeku pojedinačni segmenti
značajno duži.
Iako razlike nisu značajne, one ukazuju na to da promjene u strukturi ovog gena nisu izravno
povezane s izrastanjem dendrita, već da dolazi do promjene aktivnosti kortiko-strijatalnih
krugova povezanih s čeonom i zatiljnom moždanom korom. U linijama miševa koje nose
samo jednu zamijenjenu aminokiselinu nisu uočene značajne razlike u morfologiji
dendritičkog stabla.
Dobiveni rezultati ukazuju da su promjene koje se mogu pripisati humaniziranom obliku
Foxp2 gena vezane uz potrebu zamjene obje aminokiseline u njegovom proteinu.

Abstract (english)

It has been proposed that the FOXP2 gene has an important role in the function of
neural circuitries involved in speech processing. A protein coded by this gene differs between
chimpanzee and man in only two amino acids, which means that it is extremely conserved.
Individuals with only one functional FOXP2 allele suffer from speech impairment and have
structural changes predominantly found in the striatum.
When a human variant of the gene was experimentally introduced into the Foxp2 gene of
mice, experiments showed that this gene caused electrophysiological as well as different
behavioural changes in the experimental animals. Research studies implicated its role in
dendritic outgrowth of neurons that highly express Foxp2, like medium spiny neurons of
striatum.
The goal of this research was to analyse the morphology of medium spiny neurons in the
wild type animals using Golgi-Cox method, to determine regional differences in their
morphology throughout dorsal striatum and to see the possible effect of humanized Foxp2
gene and two additional lines of transgenic animals (Foxp2T302N and Foxp2N324S) on their
morphology.
The results showed that there were no major morphological differences between the neurons
of transgenic animals and their control group but there were regional differences in neuronal
morphology, especially in the rostral and caudal striatum where the neurons had on average
15-20% greater dendritic trees but with different topology. Accordingly, the number of
segments was proportionally increased in the caudal parts, as opposed to the rostral parts that
had longer average length of individual segments.
Although these differences were not significant, they implied structural changes influenced by
Foxp2 gene, which were not directly related to dendritic outgrowth but rather with changes in
activity of the corticostriatal loops associated with frontal and occipital cortex.
The results showed that in order to influence changes present in the humanized animals, both
amino acid changes in the protein structure are needed.

• Keywords: medicina
• Keywords (english): medicine
• Language: croatian
• URN:NBN: urn:nbn:hr:105:241533
• Study programme: Title: Biomedicine and Health Sciences; 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: 86 str.
• File origin: Born digital
• Access conditions: Open access
• Created on: 2023-05-05 08:02:23