Established by Antonello Mallamaci in 2006 at SISSA, Trieste, the LCCD presently investigates the impact of a key transcription factor mastering embryonic development of telencephalon, Foxg1, on brain function, including both fine molecular mechanisms mediating its action and the emerging “macroscopic” outcomes of it. Moreover, the LCCD works at developing precision treatments for the therapy of neuropathogenic FOXG1 haploinsufficiencies.

In last years, the LCCD Team discovered that, specifically within neocortical neurons and in addition to canonical control of transcription, Foxg1 shapes the biology of L1 retrotransposons. Specifically, while inhibiting their transcription, it unexpectedly enhances retro-transcription of their mRNAs, by counteracting two RNA helicases in charge of its repression.

Next, the LCCD Team found that Foxg1 also modulates post-transcriptional steps of gene expression, including translation, by straightly interacting with canonical players of the corresponding molecular machineries. The Team also showed that, not strictly peculiar to Foxg1, multilevel control of target gene expression apparently applies to hundreds of canonical transcription factors, an issue with deep evolutionary implications.

More recently, the LCCD Team got substantial evidence that Foxg1 may tune levels of selected protein sets, by modulating expression levels of a few, E3-ubiquitin ligase-encoding, Rnf genes and/or interacting with their protein products.

The last two topics are presently subject of further investigation.

Concerning emerging “macroscopic” effects of Foxg1 modulation in telencephalic neurons, the LCCD Team recently found that, possibly as a consequence of the reciprocal complex feedback taking place between neuronal activity and Foxg1 transcription, Foxg1 modulates the recruitability of hippocampal and amygdaloid neurons into engrams representing fear-context association. It also tunes the size of such engrams and, as expected, all that translates into an appreciable impact on the dynamics of cognitive processes. 

Temporal unfolding, molecular and neurocircuital mediators of these phenomena are subject of ongoing investigation.

A subset of patients affected by the FOXG1 syndrome are haploinsufficient for this gene. Since several years, the LCCD Team is working at developing precision, RNA-based methods for therapy of such abnormality, based of gentle stimulation of the spared allele, compliant with its fine endogenous tuning.

Years ago, the Team selected an artificial miRNA able to mildly upregulate Foxg1-mRNA in the brain of juvenile mice, by stimulating its synthesis. Later, it proved that this miRNA works also in human neocortical neurons. Moreover it found that in both species, this miRNA elicits similar changes in activity profiles of primary neuronal cultures, as detectable by a genetically encoded Ca2+ sensor.

Next, the LCCD Team considered to distribute the therapeutic intervention over distinctive steps of gene expression, in order to prevent their saturation and leave sufficient regulatory room at each level, suitable for natural endogenous tuning. For this purpose, the Team is presently working at selecting both RNA analogs and genetically encoded mid-sized RNAs, able to target FOXG1-mRNA and increase its stability or translatability.

Born in Naples in 1961, Antonello Mallamaci graduated in Pianoforte at the Conservatorio of Naples in 1985 and in Biological Sciences at the University Federico II in Naples in 1990. From 1991 to 2001, he worked at DIBIT-H San Raffaele in Milan with E. Boncinelli and had stages abroad, in the labs of R. Krumlauf, W. Wurst and J. Parnavelas. Since 2002 PI at DIBIT-HSR in Milan, in 2006 he moved to SISSA, in Trieste, where he currently serves as Full Professor of Molecular Biology and Head of the Laboratory of Cerebral Cortex Development.

During his career, AM mainly addressed molecular mechanisms controlling development and function of the anterior brain. Early on, he pioneered the study of pallial specification of the dorsal telencephalon, regionalisation of the cerebro-cortical field and appropriate sizing of distinctive areas arising from it. Next, he investigated the role of selected patterning genes in control of late cortico-cerebral histogenesis, including astrogenesis progression, neuronal morphogenesis, and neuronal excitability. More recently, he has been investigating non-canonical implication of transcription factors in post-transcriptional gene expression control, as well the impact of one of them, pattering the anterior brain, on learning processes. Meanwhile he has been developing innovative methods for treatment of glioblastoma and RNA-therapy of neuropathogenic haploinsufficiencies.

22 PhD students graduated under AM's supervision, within the framework of four different PhD programs ("Open University, Molecular and Cellular Biology Program", at H San Raffaele, Milan; "Neuroscience-Neurobiology Program", at SISSA, Trieste; "Molecular Biology JUMBO Program", at SISSA, Trieste; "Functional and Structural Genomics Program", at SISSA, Trieste).

contacts:

phone: +39 040 3787 717

email: antonello.mallamaci@sissa.it

office: room A-618 - 6th floor - Main SISSA Building, via Bonomea 265 - 34136 Trieste (TS) - Italy

Maria Ayub, PhD student, IV+ year

Elena Sabina Maftei, PhD student, IV year

Claudia Sgherza, PhD student, III year

Ayesha Ahsan, PhD student, I year

Massimo Addesse, PhD student, I year

        Pubmed-indexed publications bioRxiv manuscripts